MDPIActa Medica Okayama2079-972112112024The Change in Public Perception and Knowledge Acquisition Methods of Chronic Kidney Disease Among General Population in Okayama Prefecture, Japan268ENRyokoUmebayashiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesNatsumiMatsuoka-UchiyamaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesHitoshiSugiyamaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesKenichiShikataOkayama UniversityNaokiKashiharaKawasaki Geriatric Medical CenterHirofumiMakinoOkayama UniversityJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesHaruhito A.UchidaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesCKD public education plays a very important role in effective chronic kidney disease (CKD) countermeasure. We have been conducting CKD public education programs in Okayama Prefecture since 2007. Here, we aimed to examine the actual status of CKD perceptance and changes in CKD perceptance due to these education programs. The study was conducted on individuals who underwent health checkups at 12 medical institutions across five medical regions in Okayama Prefecture between 1 October and 30 November in 2015, 2019, and 2023. The results showed that overall CKD perceptance has improved over time (perceptance of "CKD" 4% to 7%, "chronic kidney disease" 27% to 34%, 2015 vs. 2023). "Chronic kidney disease" was more commonly recognized than "CKD", and the elderly were more aware of the disease than younger people. The CKD perceptance improved across all age groups. However, the rate of CKD perceptance is still low, especially among young people. Previously, newspapers were the second most common resource of information about CKD after television. However, the Internet has recently replaced newspapers as the second most common source of information, especially among younger people. Understanding of the exact diagnosis of CKD also remains insufficient. It is necessary to continue more effective CKD public education programs through more intelligible terminology and information sources that match the demographics of target population.No potential conflict of interest relevant to this article was reported.Fuji Technology Press Ltd.Acta Medica Okayama1883-80301712022Questionnaire Survey on COVID-19 Vaccination at Okayama University in Japan: Factors Promoting Vaccination Among Young Adults2130ENChigusaHiguchiOkayama University Health Service CenterNaomiMatsumotoDepartment of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityYoshiakiIwasakiOkayama University Health Service CenterTakashiYorifujiDepartment of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJunichiroYamazakiOkayama UniversityYasutomoNasuOkayama UniversityHirofumiMakinoOkayama UniversityCOVID-19 has been prevalent worldwide since 2019. Increasing COVID-19 vaccination coverage is an important measure to combat the disease. An online survey was conducted with university students and personnel who were vaccinated against COVID-19 at a mass vaccination event to examine the factors promoting vaccination among young adults. The online survey was conducted with persons vaccinated at Okayama University from June 5 to September 27, 2021. Although the number of those who had fever >37.5°C increased after the second vaccination compared to the first, the vaccinated persons got more satisfied after the second shot.No potential conflict of interest relevant to this article was reported.MDPIActa Medica Okayama2075-44261342023The Effect of Medical Cooperation in the CKD Patients: 10-Year Multicenter Cohort Study582ENYasuhiroOnishiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesHaruhito A.UchidaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesYoheiMaeshimaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesYukaOkuyamaJapanese Red Cross Society Himeji HospitalNozomuOtakaKagawa Prefectural Central HospitalHaruyoUjikeKagawa Prefectural Central HospitalKeikoTanakaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesHidemiTakeuchiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesKenjiTsujiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesMasashiKitagawaNational Hospital Organization Okayama Medical CenterKatsuyukiTanabeDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesHiroshiMorinagaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesMasaruKinomuraOkayama Saiseikai General HospitalShinjiKitamuraDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesHitoshiSugiyamaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesKosukeOtaNational Hospital Organization Okayama Medical CenterKeisukeMaruyamaOkayama Saiseikai General HospitalMakotoHiramatsuOkayama Saiseikai General Hospital,YoshiyukiOshiroKawasaki Medical School General Medical CenterShigeruMoriokaOkayama Central HospitalKeiichiTakiueOkayama City HospitalKazuyoshiOmoriShigei Medical Research HospitalMasakiFukushimaShigei Medical Research HospitalNaoyukiGamouJapanese Red Cross Okayama HospitalHiroshiHirataAkebono ClinicRyosukeSatoSato ClinicHirofumiMakinoOkayama UniversityJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesIntroduction: While chronic kidney disease (CKD) is one of the most important contributors to mortality from non-communicable diseases, the number of nephrologists is limited worldwide. Medical cooperation is a system of cooperation between primary care physicians and nephrological institutions, consisting of nephrologists and multidisciplinary care teams. Although it has been reported that multidisciplinary care teams contribute to the prevention of worsening renal functions and cardiovascular events, there are few studies on the effect of a medical cooperation system. Methods: We aimed to evaluate the effect of medical cooperation on all-cause mortality and renal prognosis in patients with CKD. One hundred and sixty-eight patients who visited the one hundred and sixty-three clinics and seven general hospitals of Okayama city were recruited between December 2009 and September 2016, and one hundred twenty-three patients were classified into a medical cooperation group. The outcome was defined as the incidence of all-cause mortality, or renal composite outcome (end-stage renal disease or 50% eGFR decline). We evaluated the effects on renal composite outcome and pre-ESRD mortality while incorporating the competing risk for the alternate outcome into a Fine-Gray subdistribution hazard model. Results: The medical cooperation group had more patients with glomerulonephritis (35.0% vs. 2.2%) and less nephrosclerosis (35.0% vs. 64.5%) than the primary care group. Throughout the follow-up period of 5.59 +/- 2.78 years, 23 participants (13.7%) died, 41 participants (24.4%) reached 50% decline in eGFR, and 37 participants (22.0%) developed end-stage renal disease (ESRD). All-cause mortality was significantly reduced by medical cooperation (sHR 0.297, 95% CI 0.105-0.835, p = 0.021). However, there was a significant association between medical cooperation and CKD progression (sHR 3.069, 95% CI 1.225-7.687, p = 0.017). Conclusion: We evaluated mortality and ESRD using a CKD cohort with a long-term observation period and concluded that medical cooperation might be expected to influence the quality of medical care in the patients with CKD.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama2023General Summary of Final ReportENHirofumiMakinoPresident of National University Corporation Okayama UniversityNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama2023総論ENHirofumiMakinoPresident of National University Corporation Okayama UniversityNo potential conflict of interest relevant to this article was reported.ELSEVIERActa Medica Okayama0022-22754842007The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis768781ENMasakoTabuchiDepartment of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKatsumiInoueDepartment of Pathology, Kokura Memorial HospitalHitomiUsui-KataokaDepartment of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKazukoKobayashiDepartment of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMisakoTeramotoDepartment of Pathology, Kokura Memorial HospitalKojiTakasugiDepartment of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKenichiShikataDepartment of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMasahiroYamamuraDepartment of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKenjiAndoDepartment of Cardiology, Kokura Memorial HospitalKeiichiroNishidaDepartment of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesJunkoKasaharaDepartment of Internal Medicine, Okayama Central HospitalNoriakiKumeDepartment of Cardiovascular Medicine, Kyoto University Graduate School of MedicineLuis R.LopezCorgenix, Inc.KazuakiMitsudoDepartment of Cardiovascular Medicine, Kurashiki Central HospitalMasakiyoNobuyoshiDepartment of Cardiology, Kokura Memorial HospitalTatsujiYasudaDepartment of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesToruKitaDepartment of Cardiovascular Medicine, Kyoto University Graduate School of MedicineHirofumiMakinoDepartment of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesEijiMatsuuraDepartment of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesC-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta 2-glycoprotein I (beta 2GPI), implicating oxLDL/P2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta 2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/R2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta 2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of adierosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta 2GPI complexes correlated with total cholesterol and hemoglobin Al c. Thus, the generation of CRP/oxLDL/beta 2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/R2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.No potential conflict of interest relevant to this article was reported.ElsevierActa Medica Okayama0022-22754442003Circulating oxidized LDL forms complexes with β(2)-glycoprotein I: implication as an atherogenic autoantigen716726ENKazukoKobayashiDepartment of Cell Chemistry, Okayama University Graduate School of Medicine and DentistryMakotoKishiDepartment of Cell Chemistry, Okayama University Graduate School of Medicine and DentistryTatsuyaAtsumiDepartment of Medicine II, Hokkaido University Graduate School of MedicineMaria L.BertolacciniLupus Research Unit, The Rayne Institute, St. Thomas' Hospital LondonHirofumiMakinoDepartment of Medicine and Clinical Science, Okayama University Graduate School of Medicine and DentistryNobuoSakairiDivision of Bioscience, Graduate School of Environment Earth Science, Hokkaido UniversityItaruYamamotoDepartment of Immunochemistry, Faculty of Pharmaceutical Science, Okayama UniversityTatsujiYasudaDepartment of Cell Chemistry, Okayama University Graduate School of Medicine and DentistryMunther A.KhamashtaLupus Research Unit, The Rayne Institute, St. Thomas' Hospital LondonGraham R. V.HughesLupus Research Unit, The Rayne Institute, St. Thomas' Hospital LondonTakaoKoikeDepartment of Medicine II, Hokkaido University Graduate School of MedicineDennis R.VoelkerProgram in Cell Biology, Department of Medicine, National Jewish Medical and Research CenterEijiMatsuuraDepartment of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistrybeta(2)-glycoprotein I (beta(2)-GPI) is a major antigen for antiphospholipid antibodies (Abs, aPL) present in patients with antiphospholipid syndrome (APS). We recently reported (I. Lipid Res., 42: 697, 200 1; J Lipid Res., 43: 1486, 2002) that beta(2)-GPI specifically binds to Cu2+-oxidized LDL (oxLDL) and that the beta(2)-GPI ligands are omega-carboxylated 7-ketocholesteryl esters. In the present study, we demonstrate that oxLDL forms stable and nondissociable complexes with beta(2)-GPI in serum, and that high serum levels of the complexes are associated with arterial thrombosis in APS. A conjugated ketone function at the 7-position of cholesterol as well as the omega-carboxyl function of the beta(2)-GPI ligands was necessary for beta(2)-GPI binding. The ligand-mediated noncovalent interaction of beta(2)-GPI and oxLDL undergoes a temperature- and time-dependent conversion to much more stable but readily dissociable complexes in vitro at neutral pH. In contrast, stable and nondissociable beta(2)-GPI-oxLDL complexes were frequently detected in sera from patients with APS and/or systemic lupus erythematodes. Both the presence Of beta(2)-GPI-oxLDL complexes and IgG Abs recognizing these complexes were strongly associated with arterial thrombosis. Further, these same Abs correlated with IgG immune complexes containing beta(2)-GPI or LDL.jlr Thus, the beta(2)-GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogenesis.No potential conflict of interest relevant to this article was reported.Nature PortfolioActa Medica Okayama2045-23221112021Association of blood pressure and renal outcome in patients with chronic kidney disease; a post hoc analysis of FROM-J study14990ENMarikoTsuchida-NishiwakiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceHaruhito A.UchidaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceHidemiTakeuchiDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceNoriyukiNishiwakiDepartment of Gastroenterological Surgery Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceYoheiMaeshimaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceChieSaitoDepartment of Nephrology, Faculty of Medicine, University of TsukubaHitoshiSugiyamaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical ScienceIchieiNaritaDivision of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental ScienceTsuyoshiWatanabeTokyo-Kita Medical CenterSeiichiMatsuoNagoya UniversityHirofumiMakinoOkayama UniversityAkiraHishidaYaizu City HospitalKunihiroYamagataDepartment of Nephrology, Faculty of Medicine, University of TsukubaIt is well-known that hypertension exacerbates chronic kidney disease (CKD) progression, however, the optimal target blood pressure (BP) level in patients with CKD remains unclear. This study aimed to assess the optimal BP level for preventing CKD progression. The risk of renal outcome among different BP categories at baseline as well as 1 year after, were evaluated using individual CKD patient data aged between 40 and 74 years from FROM-J [Frontier of Renal Outcome Modifications in Japan] study. The renal outcome was defined as >= 40% reduction in estimated glomerular filtration rate to<60 mL/min/1.73 m(2), or a diagnosis of end stage renal disease. Regarding baseline BP, the group of systolic BP (SBP) 120-129 mmHg had the lowest risk of the renal outcome, which increased more than 60% in SBP<greater than or equal to>130 mmHg group. A significant increase in the renal outcome was found only in the group of diastolic BP >= 90 mmHg. The group of BP<130/80 mmHg had a benefit for lowering the risk regardless of the presence of proteinuria, and it significantly reduced the risk in patients with proteinuria. Achieving SBP level<130 mmHg after one year resulted in a 42% risk reduction in patients with SBP level >= 130 mmHg at baseline. Targeting SBP level<130 mmHg would be associated with the preferable renal outcome.Clinical Trial Registration-URL: https://www.umin.ac.jp/ctr/. Unique identifier: UMIN000001159 (16/05/2008).No potential conflict of interest relevant to this article was reported.Nature ResearchActa Medica Okayama2045-23221112021Exploratory classification of clinical phenotypes in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis using cluster analysisENHarukiWatanabeGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityKen-eiSadaGraduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityMasayoshiHarigaiDepartment of Rheumatology, Tokyo Women’s Medical University School of MedicineKoichiAmanoDepartment of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical UniversityHiroakiDobashiDivision of Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa UniversityYoshinariTakasakiDepartment of Internal Medicine and Rheumatology, Juntendo University School of MedicineShouichiFujimotoDepartment of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of MiyazakiTatsuyaAtsumiDepartment of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityKunihiroYamagataDepartment of Nephrology, Faculty of Medicine, University of TsukubaSakaeHommaDepartment of Advanced and Integrated Interstitial Lung Diseases Research, School of Medicine, Toho UniversityYoshihiroArimuraDepartment of Nephrology and Rheumatology, Kyorin University School of MedicineHirofumiMakinoOkayama UniversityResearch Committee of Intractable Vasculitis Syndrome (JPVAS) & Research Committee of Intractable Renal Disease of the Ministry of Health, Labour, and Welfare of JapanA novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n=8) and proteinase 3-ANCA-positive (n=41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n=47); cutaneous (n=36); renal (n=256), non-renal (n=33); and both ENT and cutaneous symptoms (n=6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n=42), without s-Cr elevation (<1.3 mg/dL) (n=157), s-Cr elevation (<greater than or equal to>1.3 mg/dL) with high CRP (>10 mg/dL) (n=71), or s-Cr elevation (>= 1.3 mg/dL) without high CRP (<= 10 mg/dL) (n=157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.No potential conflict of interest relevant to this article was reported.BMCActa Medica Okayama1478-63542212020Treatment-related damage in elderly-onset ANCA-associated vasculitis: safety outcome analysis of two nationwide prospective cohort studies236ENKen-EiSadaDepartment of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKeijiOhashiDepartment of Clinical Epidemiology, Kochi Medical School, Kochi UniversityYosukeAsanoDepartment of Clinical Epidemiology, Kochi Medical School, Kochi UniversityKeigoHayashiDepartment of Clinical Epidemiology, Kochi Medical School, Kochi UniversityMichikoMorishitaDepartment of Clinical Epidemiology, Kochi Medical School, Kochi UniversityHarukiWatanabeDepartment of Clinical Epidemiology, Kochi Medical School, Kochi UniversityYoshinoriMatsumotoDepartment of Clinical Epidemiology, Kochi Medical School, Kochi UniversityShouichiFujimotoDepartment of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of MiyazakiYoshinariTakasakiDepartment of Internal Medicine and Rheumatology, Juntendo University School of MedicineKunihiroYamagataDepartment of Nephrology, Faculty of Medicine, University of TsukubaShogoBannoDepartment of Nephrology and Rheumatology, Aichi Medical UniversityHiroakiDobashiDivision of Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa UniversityKoichiAmanoDepartment of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical UniversityMasayoshiHarigaiDepartment of Rheumatology, Tokyo Women’s Medical University School of MedicineYoshihiroArimuraDepartment of Nephrology and Rheumatology, Kyorin University School of MedicineHirofumiMakinoOkayama Universitythe Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) and the Research Committee of Intractable Renal Disease of the Ministry of Health, Labour, and Welfare of JapanBackground</br>
It is not elucidated that there is treatment-related damage in elderly patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).</br>
Methods</br>
Elderly (≥ 75 years of age) patients were enrolled from two nationwide prospective inception cohort studies. The primary outcome was 12-month treatment-related Vasculitis Damage Index (VDI) score. Secondary outcomes included serious infections within 6 months, total VDI score, remission, and relapse. Patient characteristics and outcomes were compared across three different initial glucocorticoid (GC) dose groups: high-dose, prednisolone (PSL) ≥ 0.8 mg/kg/day; medium-dose, 0.6 ≤ PSL < 0.8 mg/kg/day; and low-dose, PSL < 0.6 mg/kg/day.</br>
Results</br>
Of the 179 eligible patients, the mean age was 80.0 years; 111 (62%) were female. The mean Birmingham Vasculitis Activity Score was 16.1. Myeloperoxidase-ANCA findings were positive in 168 (94%) patients, while proteinase 3-ANCA findings were positive in 11 (6%). The low-dose group was older and had higher serum creatinine levels than the other groups. There were no statistically significant intergroup differences in remission or relapse, whereas serious infection developed more frequently in the high-dose (29 patients [43%]) than the low-dose (13 patients [22%]) or medium-dose (10 patients [19%]) groups (p = 0.0007). Frequent VDI items at 12 months included hypertension (19%), diabetes (13%), atrophy and weakness (13%), osteoporosis (8%), and cataracts (8%). Logistic regression analysis revealed that GC dose at 12 months (odds ratio, 1.14; 95% confidence interval, 1.00–1.35) was a predictor for diabetes.</br>
Conclusion</br>
A reduced initial GC dose with rapid reduction might be required to ensure the safe treatment of elderly AAV patients.No potential conflict of interest relevant to this article was reported.WileyActa Medica Okayama2040-11161222020Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)207216ENKenichiShikataCenter for Innovative Clinical Medicine, Okayama University HospitalMasakazuHanedaDivision of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical UniversityToshiharuNinomiyaDepartment of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu UniversityDaisukeKoyaDepartment of Diabetology & Endocrinology, Kanazawa Medical UniversityYoshikiSuzukiHealth Administration Center, Niigata UniversityDaisukeSuzukiSuzuki Diabetes ClinicHitoshiIshidaResearch Center for Health Care, Nagahama City HospitalHiroakiAkaiDivision of Metabolism and Diabetes, Tohoku Medical and Pharmaceutical UniversityYasuhikoTominoDivision of Nephrology, Department of Internal Medicine, Juntendo University Faculty of MedicineTakashiUzuDivision of Nephrology, Department of Medicine, Nippon Life HospitalMotonobuNishimuraDepartment of Diabetes and Endocrinology, National Hospital Organization Chiba‐East National HospitalShiroMaedaDepartment of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the RyukyusDaisukeOgawaOkayama Diabetes and Neurology ClinicSatoshiMiyamotoCenter for Innovative Clinical Medicine, Okayama University HospitalHirofumiMakinoOkayama Universitythe Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) collaborative groupAims/Introduction</br>
We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD).</br>
Materials and Methods</br>
The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population.</br>
Results</br>
The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups.</br>
Conclusions</br>
The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease.No potential conflict of interest relevant to this article was reported.Taylor & FrancisActa Medica Okayama1439-75952652016Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study730737ENKen-eiSada Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasayoshiHarigaiDepartment of Rheumatology, Graduate School of Medical and Dental Sciences , Tokyo Medical and Dental UniversityKoichiAmanoDepartment of Rheumatology and Clinical Immunology , Saitama Medical Center, Saitama Medical UniversityTatsuyaAtsumiDivision of Rheumatology, Endocrinology and Nephrology at the Graduate School of Medicine , Hokkaido UniversityShouichiFujimotoDepartment of Hemovascular Medicine and Artificial Organs, Faculty of Medicine , Miyazaki UniversityYukioYuzawaDepartment of Nephrology , Fujita Health University School of MedicineYoshinariTakasakiDepartment of Internal Medicine and Rheumatology , Juntendo University School of MedicineShogoBannoDivision of Rheumatology and Nephrology, Department of Internal Medicine , Aichi Medical University School of MedicineTakahikoSugiharaTokyo Metropolitan Geriatric Hospital and Institute of GerontologyMasakiKobayashiDepartment of Nephrology , Tokyo Medical University Ibaraki Medical CenterJoichiUsuiDepartment of Nephrology, Faculty of Medicine , University of TsukubaKunihiroYamagataDepartment of Nephrology, Faculty of Medicine , University of TsukubaSakaeHommaDepartment of Respiratory Medicine , Toho University Omori Medical CenterHiroakiDobashiDivision of Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine , Kagawa University NaotakeTsuboiDepartment of Nephrology, Internal Medicine , Nagoya University Graduate School of MedicineAkihiroIshizuFaculty of Health Sciences , Hokkaido UniversityHitoshiSugiyamaDepartment of Chronic Kidney Disease and Peritoneal Dialysis , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences YasunoriOkadaDepartment of Pathology , Keio University School of MedicineYoshihiroArimuraNephrology and Rheumatology, First Department of Internal Medicine , Kyorin University School of MedicineSeiichiMatsuoDepartment of Nephrology, Internal Medicine , Nagoya University Graduate School of MedicineHirofumiMakinoOkayama University HospitalOBJECTIVE:
To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
METHODS:
Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated.
RESULTS:
According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival.
CONCLUSIONS:
The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812922017岡山県健診受診者の慢性腎臓病（CKD）認知度〜 2015年度〜101105ENHaruhito A.UchidaDepartment of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesHitoshiSugiyamaDepartment of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesMasashiMiyazakiSaiwaicho Memorial HospitalJunWadaDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKenichiShikataCenter for Innovative Clinical Medicine, Okayama University HospitalNaokiKashiharaDepartment of Nephrology/Hypertension, Kawasaki Medical SchoolHirofumiMakinoDepartment of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Public education programs about chronic kidney disease (CKD) have been performed in Okayama, Japan for the past 10 years. The present study investigated the perception of CKD in a general population in Okayama. In October and November 2015, a questionnaire survey was distributed by 12 medical centers in five medical districts in Okayama prefecture. A total of 7,022 respondents who underwent their physical checkup at these centers answered the questionnaire. In response to a questionnaire item asking about the respondent's familiarity with the term "CKD," only 4% of the respondents answered "know it well" and 10% answered "unfamiliar." In contrast, in response to a questionnaire item asking about the respondent's familiarity with "chronic kidney disease," 27% answered "know it well" and 38% answered "unfamiliar." The leading avenue by which the respondents learned about CKD/chronic kidney disease was television, followed by newspapers, magazines, and a family doctor or nurse. The leading component which the respondents considered essential for the diagnosis of CKD/chronic kidney disease was proteinuria. A stratified analysis demonstrated a higher recognition of “CKD" or “chronic kidney disease" in the medical districts in northern Okayama prefecture compared to southern Okayama prefecture. These results indicated that the awareness of CKD in Okayama prefecture is still inadequate. Many people did not appear to realize that the term “CKD" represents
"chronic kidney disease". Further continuous public education efforts are required to enlighten people about CKD/chronic kidney disease.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812912017臨床研究中核病院と岡山大学4549ENHirofumiMakinoOkayama University Executive Director (University Hospital)No potential conflict of interest relevant to this article was reported.PUBLIC LIBRARY SCIENCEActa Medica Okayama1932-6203932014Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathye92647ENMayuWatanabeAtsukoNakatsukaKazutoshiMurakamiKentaroInoueTakahiroTeramiChigusaHiguchiAkihiroKatayamaSanaeTeshigawaraJunEguchiDaisukeOgawaEijiroWatanabeJunWadaHirofumiMakinoPhosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt−/−mice, the glomerular hypertrophy and albuminuria in Pemt−/− mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt−/− diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.No potential conflict of interest relevant to this article was reported.PUBLIC LIBRARY SCIENCEActa Medica Okayama1932-6203912014Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Linese85594ENDaisukeOgawaJunEguchiJunWadaNaotoTeramiTakashiHatanakaHiromiTachibanaAtsukoNakatsukaChikageSato HoriguchiNaokoNishiiHirofumiMakinoNuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-γ (PPARγ) and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.No potential conflict of interest relevant to this article was reported.Nature Publishing GroupActa Medica Okayama2045-232252015Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis16920ENAkihiroKatayamaAtsukoNakatsukaJunEguchiKazutoshiMurakamiSanaeTeshigawaraMotokoKanzakiTomokazuNunoueKazuyukiHidaNozomuWadaTetsuyaYasunakaFusaoIkedaAkinobuTakakiKazuhideYamamotoHiroshiKiyonariHirofumiMakinoJunWadaNonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.No potential conflict of interest relevant to this article was reported.AlphaMed PressActa Medica Okayama1066-50993332015Single adult kidney stem/progenitor cells reconstitute three-dimensional nephron structures in vitro.774784ENShinjiKitamuraHiroyukiSakuraiHirofumiMakinoThe kidneys are formed during development from two distinct primordial tissues, the metanephric mesenchyme and the ureteric bud. The metanephric mesenchyme develops into the kidney nephron, the minimal functional unit of the kidney. A nephron consists of several segments and regulates water, electrolyte, and acid-base homeostasis in addition to secreting certain hormones. It has been predicted that the kidney will be among the last organs successfully regenerated in vitro due to its complex structure and multiple functions. Here, we show that adult kidney stem/progenitor cells (KS cells), derived from the S3 segment of adult rat kidney nephrons, can reconstitute a three-dimensional kidney-like structure in vitro. Kidney-like structures were formed when a cluster of KS cells was suspended in an extracellular matrix gel and cultured in the presence of several growth factors. Morphological analyses revealed that these kidney-like structures contained every substructure of the kidney, including glomeruli, proximal tubules, the loop of Henle, distal tubules, and collecting ducts, but no vasculature. Our results demonstrate that a cluster of tissue stem/progenitor cells has the ability to reconstitute the minimum unit of its organ of origin by differentiating into specialized cells in the correct location. This process differs from embryonic kidney development, which requires the mutual induction of two different populations of progenitors, metanephric mesenchymal cells and ureteric bud cells.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812722015第49回糖尿病学の進歩「糖尿病教育とチーム医療の実践を目指して」開催報告167168ENHirofumiMakinoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6912015ONO-1301, a Sustained-Release Prostacyclin Analog, Ameliorates the Renal Alterations in a Mouse Type 2 Diabetes Model Possibly Through Its Protective Effects on Mesangial Cells115ENHiroyukiWatataniHirokoYamasakiYoheiMaeshimaTatsuyoNasuNorikazuHinamotoHaruyoUjikeHitoshiSugiyamaYoshikiSakaiKatsuyukiTanabeHirofumiMakinoOriginal Article10.18926/AMO/53117Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A2 synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-β1, α-smooth muscle actin (α-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-β, type IV collagen, α-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI2) receptor-mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells.No potential conflict of interest relevant to this article was reported.Academic Press Inc Elsevier ScienceActa Medica Okayama0006-291X44712014Hypoxia-inducible factor 1 alpha regulates branching morphogenesis during kidney development108114ENKenjiTsujiShinjiKitamuraHirofumiMakinoThe kidneys are exposed to hypoxic conditions during development. Hypoxia-inducible factor (HIF), an important mediator of the response to hypoxia, is believed to have an important role in development. However, the relationship between HIF and branching morphogenesis has not been elucidated clearly. In this study, we examined whether HIF regulates kidney development. We harvested kidneys from day 13 rat embryos (E13K5) and cultured the organs under normoxic (20% 02/5% CO2) or hypoxic (5% 02/5% CO2) conditions. We evaluated the kidneys based on morphology and gene expression. El3K5 cultured under hypoxic conditions had significantly more ureteric bud (UB) branching than the E13Ks cultured under normoxic conditions. In addition, the mRNA levels of GDNF and GDNF receptor (GFR-alpha l), increased under hypoxic conditions in E13K5. When we cultured E13Ks( with the HIF-1 alpha inhibitor digoxin or with siRNA targeting HIF-l alpha under hypoxic conditions, we did not observe increased UB branching. In addition, the expression of GDNF and GFR-alpha 1 was inhibited under hypoxic conditions when the kidneys were treated with siRNA targeting HIF-1 alpha. We also elucidated that hypoxia inhibited UB cell apoptosis and promoted the expression of FGF7 mRNA levels in metanephric mesenchymal (MM) cells in vitro. These findings suggest that hypoxic condition has important roles in inducing branching morphogenesis during kidney development. Hypoxia might mediate branching morphogenesis via not only GDNF/Ret but also FGF signaling pathway.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama62013Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes233240ENTakahiroTeramiJunWadaKentaroInoueAtsukoNakatsukaDaisukeOgawaSanaeTeshigawaraKazutoshiMurakamiAkihiroKatayamaJunEguchiHirofumiMakinoPurpose: Urinary angiotensinogen has been reported as a marker for the activation of intrarenal renin–angiotensin system (RAS) in various kidney diseases. To investigate the importance of urinary angiotensinogen in diabetic nephropathy, we compared the urinary levels of angiotensinogen, albumin, and α1-microglobulin.
Materials and methods: Japanese patients with type 2 diabetes at various stages of nephropathy (n=85) were enrolled, and we measured albumin/creatinine ratio (ACR) and urinary excretion of angiotensinogen and α1-microglobulin. We also compared the clinical data of the patients treated with or without angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (RAS inhibitors [+], n=51; RAS inhibitors [−], n=34).
Results: Urinary angiotensinogen levels positively correlated with ACR (r =0.367, P=3.84×10-4) and urinary α1-microglobulin (r=0.734, P=1.32 × 10-15), while they negatively correlated with estimated glomerular filtration ratio (eGFR) (r=−0.350, P=1.02 × 10-3) and high-density lipoprotein cholesterol (r=−0.216, P=0.049). Multiple regression analysis was carried out to predict urinary angiotensinogen levels by employing eGFR, ACR, and urinary α1-microglobulin as independent variables; only urinary α1-microglobulin entered the regression equation at a significant level. Although ACR was higher in the RAS inhibitors (+) group, urinary α1-microglobulin and angiotensinogen did not show significant increase in the RAS inhibitors (+) group.
Conclusion: Urinary angiotensinogen is well correlated with urinary α1-microglobulin and reflected the tubular injuries which may be associated with the intrarenal RAS activation in patients with type 2 diabetes.No potential conflict of interest relevant to this article was reported.Public Library ScienceActa Medica Okayama1932-62038102013Urinary Fetuin-A Is a Novel Marker for Diabetic Nephropathy in Type 2 Diabetes Identified by Lectin MicroarrayENKentaroInoueJunWadaJunEguchiAtsukoNakatsukaSanaeTeshigawaraKazutoshiMurakamiDaisukeOgawaTakahiroTeramiAkihiroKatayamaAtsuhitoToneIzumiIsedaKazuyukiHidaMasaoYamadaTomohisaOgawaHirofumiMakinoWe analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Sia alpha 2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40 +/- 0.43; A2, 0.60 +/- 0.53; A3 1.57 +/- 1.13 ng/gCr; p = 7.29x10(-8)) and of GFR stages (G1, 0.39 +/- 0.39; G2, 0.49 +/- 0.45; G3, 1.25 +/- 1.18; G4, 1.34 +/- 0.80 ng/gCr; p = 3.89x10(-4)). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR<60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881-11.844) and 3.739 (1.785-7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama72013Long-term effect of cinacalcet hydrochloride on abdominal aortic calcification in patients on hemodialysis with secondary hyperparathyroidism2533ENKazunoriNakayamaKazushiNakaoYujiTakatoriJunkoInoueShoichirouKojoShigeruAkagiMasakiFukushimaJunWadaHirofumiMakinoBackground: Secondary hyperparathyroidism (SHPT) is one of the common complications in dialysis patients, and is associated with increased risk of vascular calcification. The effects of cinacalcet hydrochloride treatment on bone and mineral metabolism have been previously reported, but the benefit of cinacalcet on vascular calcification remains uncertain. The aim of this study was to evaluate the impact of cinacalcet on abdominal aortic calcification in dialysis patients.
Subjects and methods: Patients were on maintenance hemodialysis with insufficiently controlled SHPT (intact parathyroid hormone [PTH] >180 pg/mL) by conventional therapies. All subjects were initially administered 25 mg cinacalcet daily, with concomitant use of calcitriol analogs. Abdominal aortic calcification was annually evaluated by calculating aortic calcification area index (ACAI) using multidetector computed tomography (MDCT), from 12 months before to 36 months after the initiation of cinacalcet therapy.
Results: Twenty-three patients were analyzed in this study. The mean age was 59.0±8.7 years, 34.8% were women, and the mean dialysis duration was 163.0±76.0 months. After administration of cinacalcet, serum levels of intact PTH, phosphorus, and calcium significantly decreased, and mean Ca × P values significantly decreased from 67.4±7.9 mg2/dL2 to 52±7.7 mg2/dL2. Although the ACAI value did not decrease during the observation period, the increase in ACAI between 24 months and 36 months after cinacalcet administration was significantly suppressed.
Conclusion: Long-term administration of cinacalcet was associated with reduced progression of abdominal aortic calcification, and achieving appropriate calcium and phosphorus levels may reduce the rates of cardiovascular events and mortality in patients on hemodialysis.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0303-72073811-22013Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells815ENTomohiroTerasakaFumioOtsukaNaokoTsukamotoEriNakamuraKenichiInagakiKishioTomaKanakoOgura-OchiChristineGlidewell-KenneyMark A.LawsonHirofumiMakinoReproduction is integrated by interaction of neural and hormonal signals converging on hypothalamic neurons for controlling gonadotropin-releasing hormone (GnRH). Kisspeptin, the peptide product of the kiss1 gene and the endogenous agonist for the GRP54 receptor, plays a key role in the regulation of GnRH secretion. In the present study, we investigated the interaction between kisspeptin, estrogen and BMPs in the regulation of GnRH production by using mouse hypothalamic GT1-7 cells. Treatment with kisspeptin increased GnRH mRNA expression and GnRH protein production in a concentration-dependent manner. The expression levels of kiss1 and GPR54 were not changed by kisspeptin stimulation. Kisspeptin induction of GnRH was suppressed by co-treatment with BMPs, with BMP-4 action being the most potent for suppressing the kisspeptin effect. The expression of kisspeptin receptor, GPR54, was suppressed by BMPs, and this effect was reversed in the presence of kisspeptin. It was also revealed that BMP-induced Smad1/5/8 phosphorylation and Id-1 expression were suppressed and inhibitory Smad6/7 was induced by kisspeptin. In addition, estrogen induced GPR54 expression, while kisspeptin increased the expression levels of ER alpha. and ER beta, suggesting that the actions of estrogen and kisspeptin are mutually enhanced in GT1-7 cells. Moreover, kisspeptin stimulated MAPKs and AKT signaling, and ERK signaling was functionally involved in the kisspeptin-induced GnRH expression. BMP-4 was found to suppress kisspeptin-induced GnRH expression by reducing ERK signaling activity. Collectively, the results indicate that the axis of kisspeptin-induced GnRH production is bi-directionally controlled, being augmented by an interaction between ER alpha/beta and GPR54 signaling and suppressed by BMP-4 action in GT1-7 neuron cells.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6842014Factors Associated with Remission and/or Regression of Microalbuminuria in Type 2 Diabetes Mellitus235241ENTetsuichiroOnoKenichiShikataMikakoObikaNobuyukiMiyatakeRyoKoderaDaisyoHirotaJunWadaHitomiKataokaDaisukeOgawaHirofumiMakinoOriginal Article10.18926/AMO/52789The aim of this study was to clarify the factors associated with the remission and/or regression of microalbuminuria in Japanese patients with type 2 diabetes mellitus. We retrospectively analyzed the data of 130 patients with type 2 diabetes mellitus with microalbuminuria for 2-6 years (3.39±1.31 years). Remission was defined as improving from microalbuminuria to normoalbuminuria using the albumin/creatinine ratio (ACR), and regression of microalbuminuria was defined as a decrease in ACR of 50% or more from baseline. Progression of microalbuminuria was defined as progressing from microalbuminuria to overt proteinuria during the follow-up period. Among 130 patients with type 2 diabetes mellitus with microalbuminuria, 57 and 13 patients were defined as having remission and regression, respectively, while 26 patients progressed to overt proteinuria. Sex (female), higher HDL cholesterol and lower HbA1c were determinant factors associated with remission/regression of microalbuminuria by logistic regression analysis. Lower systolic blood pressure (SBP) was also correlated with remission/regression, but not at a significant level. These results suggest that proper control of blood glucose, BP and lipid profiles may be associated with remission and/or regression of type 2 diabetes mellitus with microalbuminuria in clinical practice.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6842014Renal Distribution of Vasohibin-1 in Patients with Chronic Kidney Disease219233ENNorikazuHinamotoYoheiMaeshimaDaisukeSaitoHirokoYamasakiKatsuyukiTanabeTatsuyoNasuHiroyukiWatataniHaruyoUjikeMasaruKinomuraHitoshiSugiyamaHikaruSonodaNaokiKanomataYasufumiSatoHirofumiMakinoOriginal Article10.18926/AMO/52788Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus
(r＝0.48, p＝0.001) or cortex (r＝0.64, p＜0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r＝0.34, p＝0.02), 3) the glomerular VEGFR-2+ area and the number of VASH-1+ cells in the glomerulus (r＝0.44, p＝0.01) or medulla (r＝0.63, p＝0.01). These results suggest that the renal levels of VASH-1 may be affected by local inflammation, crescentic lesions and VEGFR-2.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama1342-17511712013Current status of the treatment of microscopic polyangiitis and granulomatosis with polyangiitis in Japan5158ENKoichiSugiyamaKen-eiSadaMichikoKurosawaJunWadaHirofumiMakinoThis study aimed to describe the epidemiologic characteristics of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan.
We used the database of the Ministry of Health, Labour and Welfare (MHLW) from 2006 to 2008, and analyzed data from 938 patients (MPA = 697, GPA = 241) who fulfilled the MHLW diagnostic criteria and had registered within a year after onset.
The mean ages of the MPA and GPA patients were 69.4 +/- A 0.4 and 58.4 +/- A 1.1 years, respectively. Renal (86.9 %), chest (73.7 %), and nervous system (45.2 %) symptoms were common in MPA patients. Ear, nose, and throat (86.7 %), chest (78.0 %), and renal (60.6 %) symptoms were frequently observed in GPA patients. The concomitant use of cyclophosphamide (CY) with corticosteroids was observed in 22.2 % of the MPA patients and 58.5 % of the GPA patients. In multivariate analysis, the concomitant use of CY was associated with a younger age and pulmonary hemorrhage in MPA patients, and the avoidance of CY was associated with nervous system symptoms and rapidly progressive glomerulonephritis in GPA patients. Plasma exchanges were inducted in 5.2 % of the MPA patients and 4.1 % of the GPA patients. The addition of plasma exchange was associated with elevation of the serum creatinine level in patients with both MPA and GPA.
A dominance of MPA and a reduced frequency of renal involvement in GPA patients may be significant features of the Japanese population. Clinical practice relating to MPA and GPA in Japan can be characterized as follows: CY is used less commonly, and plasma exchange is employed for patients with deteriorated renal function.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama1342-17511652012Mizoribine, tacrolimus, and corticosteroid combination therapy successfully induces remission in patients with lupus nephritis760766ENHidetoshiKagawaTsutomuHiromasaTakayukiHaraAyakoTakakiRyutaroYamanakaKen-eiSadaHirofumiMakinoConventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.
We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.
All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.
This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.No potential conflict of interest relevant to this article was reported.Public Library ScienceActa Medica Okayama1932-6203822013A Decreased Level of Serum Soluble Klotho Is an Independent Biomarker Associated with Arterial Stiffness in Patients with Chronic Kidney DiseaseENMasashiKitagawaHitoshiSugiyamaHiroshiMorinagaTatsuyukiInoueKeiichiTakiueAyuOgawaToshioYamanariYokoKikumotoHaruhito AdamUchidaShinjiKitamuraYoheiMaeshimaKazufumiNakamuraHiroshiItoHirofumiMakinoBackground: Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD).
Methods: We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification.
Results: The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV >= 1400 cm/sec, atherosclerosis defined as maximum IMT >= 1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075).
Conclusions: Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812612014糖尿病の腎臓においてcholecystokininはマクロファージに対する抗炎症作用を介した新規の保護効果を発揮する16ENSatoshiMiyamotoKenichiShikataKyokoMiyasakaShinichiOkadaMotofumiSasakiRyoKoderaDaishoHirotaNobuoKajitaniTetsuharuTakatsukaHitomiKataoka UsuiShingoNishishitaChikageHoriguchi SatoAkihiroFunakoshiHisakazuNishimoriHaruhito AdamUchidaDaisukeOgawaHirofumiMakinoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6812014Lifestyle Modification Is Associated with Improving Estimated Glomerular Filtration Rate (eGFR) and Proteinuria in Japanese with Proteinuria4346ENNobuyukiMiyatakeKenichiShikataHirofumiMakinoTakeyukiNumataShort Communication10.18926/AMO/52143The link between lifestyle modification and changes in both proteinuria and estimated glomerular filtration
rates (eGFRs) was evaluated in Japanese subjects with proteinuria who were not taking medications.
We used data from 51 men (35.8±10.0 years) and 74 women (38.0±11.0 years) with proteinuria at baseline and a 1-year follow up. eGFR was defined by a new equation developed specifically for Japanese subjects. Subjects were given advice for dietary and lifestyle improvement at the initial appointment. At the 1-year follow up, eGFR was increased in both sexes, but not at significant levels. (men:p＝0.7709, women:p＝0.2180). Proteinuria was also improved in many subjects. A decrease in proteinuria may be associated with improving eGFR in Japanese.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6812014Mizoribine Inhibits the Proliferation of Renal Stem/Progenitor Cells by G1/S Arrest during Renal Regeneration715ENNaoyaHorimotoShinjiKitamuraKenjiTsujiHirofumiMakinoOriginal Article10.18926/AMO/52138Immunosuppressive agents are generally administered to treat kidney diseases. However, it is unclear whether renal stem/progenitor cells are directly affected by the immunosuppressive agents. We used normal rat kidney cells, ureteric bud cells and rat kidney stem/progenitor cells in this study. Mizoribine (MZR), cyclophosphamide (CPA) and cyclosporine (CyA) were added to the culture media of these cells. We evaluated the effects of these immunosuppressive agents on cell proliferation using an electrical cell-substrate impedance sensing system (ECIS) and their effects on the process of renal regeneration using the ischemia-reperfusion (I/R) injury rat model. The ECIS data showed that proliferation
of each of the 3 types of cells was significantly suppressed by MZR. MZR treatment enhanced renal tubular injury in ischemia-reperfusion (I/R) injured rats, and significantly decreased levels of M-phase cells and Nestin-positive cells. These results suggested that MZR inhibits the cell cycle of renal stem/progenitor cells;thus, physicians should take note that MZR might affect not only inflammation but also renal regeneration.No potential conflict of interest relevant to this article was reported.Biomed Central LtdActa Medica Okayama1471-2369142013Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney diseaseENYukoKuroseJunWadaMotokoKanzakiSanaeTeshigawaraAtsukoNakatsukaKazutoshiMurakamiKentaroInoueTakahiroTeramiAkihiroKatayamaMayuWatanabeChigusaHiguchiJunEguchiNobuyukiMiyatakeHirofumiMakinoBackground: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (T(H)1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1).
Methods: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n = 182).
Results: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 +/- 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r = 0.227, p = 0.002), creatinine (r = 0.175, p = 0.018), urea nitrogen (r = 0.162, p = 0.028) and osmotic pressure (r = 0.187, p = 0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.188, p = 0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p = 0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3.
Conclusion: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.No potential conflict of interest relevant to this article was reported.SpringerActa Medica Okayama1342-17511652012Phenotypic change of macrophages in the progression of diabetic nephropathy; sialoadhesin-positive activated macrophages are increased in diabetic kidney739748ENRyoNagaseNobuoKajitaniKenichiShikataDaisukeOgawaRyoKoderaShinichiOkadaYuichiKidoHirofumiMakinoInflammatory process is involved in pathogenesis of diabetic nephropathy, although the activation and phenotypic change of macrophages in diabetic kidney has remained unclear. Sialoadhesin is a macrophage adhesion molecule containing 17 extracellular immunoglobulin-like domains, and is an I-type lectin which binds to sialic acid ligands expressed on hematopoietic cells. The aim of this study is to clarify the activation and phenotypic change of macrophages in the progression of diabetic nephropathy.
We examined the expression of surface markers for pan-macrophages, resident macrophages, sialoadhesin, major histocompatibility complex class II and alpha-smooth muscle actin in the glomeruli of diabetic rats using immunohistochemistry at 0, 1, 4, 12, and 24 weeks after induction of diabetes by streptozotocin. Expression of type IV collagen and the change of mesangial matrix area were also measured. The mechanism for up-regulated expression of sialoadhesin on macrophages was evaluated in vitro.
The number of macrophages was increased in diabetic glomeruli at 1 month after induction of diabetes and the increased number was maintained until 6 months. On the other hand, sialoadhesin-positive macrophages were increased during the late stage of diabetes concomitantly with the increase of alpha-smooth muscle actin-positive mesangial cells, mesangial matrix area and type IV collagen. Gene expression of sialoadhesin was induced by stimulation with interleukin (IL)-1 beta and tumor necrosis factor-alpha but not with IL-4, transforming growth factor-beta and high glucose in cultured human macrophages.
The present findings suggest that sialoadhesin-positive macrophages may contribute to the progression of diabetic nephropathy.No potential conflict of interest relevant to this article was reported.Biomed Central LtdActa Medica Okayama1471-2369132012The serum vaspin levels are reduced in Japanese chronic hemodialysis patientsENJunkoInoueJunWadaSanaeTeshigawaraKazuyukiHidaAtsukoNakatsukaYujiTakatoriShoichirouKojoShigeruAkagiKazushiNakaoNobuyukiMiyatakeJohn F.McDonaldHirofumiMakinoBackground: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients.
Methods: Healthy Japanese control volunteers (control; n = 95, 49.9 +/- 6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4 +/- 10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system.
Results: The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (> 10 ng/ml; Vaspin(High) group), while the rest of the population exhibited lower levels (< 3 ng/ml; Vaspin(Low) group). By comparing the patients in the Vaspin(Low) group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87 +/- 0.24 ng/ml) than in the HD patients (0.32 +/- 0.15 ng/ml) (p < 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects.
Conclusions: The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin(Low) group.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6732013Cell Cycle Abnormality in Metabolic Syndrome and Nuclear Receptors as an Emerging Therapeutic Target129134ENAtsukoNakatsukaJunWadaHirofumiMakinoReview10.18926/AMO/50405In recent years, many researchers have emphasized the importance of metabolic syndrome based on its increasing prevalence and its adverse prognosis due to associated chronic vascular complications. Upstream of a cluster of metabolic and vascular disorders is the accumulation of visceral adipose tissue, which plays a central role in the pathophysiology. In the accumulation of adipose tissues, cell cycle regulation is tightly linked to cellular processes such as proliferation, hypertrophy and apoptosis. In addition, various cell cycle abnormalities have also been observed in other tissues, such as kidneys and the cardiovascular system, and they are critically involved in the progression of disease. Here, we discuss cell cycle abnormalities in metabolic syndrome in various tissues. Furthermore, we describe the role of nuclear receptors in cell growth and survival, and glucose and lipid metabolism in the whole body. Therapeutic strategies for modulating various cell cycles in metabolic disorders by targeting nuclear receptors may overcome obesity and its chronic vascular complications in the future.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0012-179761112012Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex28232832ENAtsukoNakatsukaJunWadaIzumiIsedaSanaeTeshigawaraKanjiHigashioKazutoshiMurakamiMotokoKanzakiKentaroInoueTakahiroTeramiAkihiroKatayamaKazuyukiHidaJunEguchiChikage SatoHoriguchiDaisukeOgawaYasushiMatsukiRyujiHiramatsuHideoYagitaShigeruKakutaYoichiroIwakuraHirofumiMakinoIt is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 2012No potential conflict of interest relevant to this article was reported.Biomed Central LtdActa Medica Okayama1471-236913142012Acatalasemic mice are mildly susceptible to Acatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosisENKeiichiTakiueHitoshiSugiyamaTatsuyukiInoueHiroshiMorinagaYokoKikumotoMasashiKitagawaShinjiKitamuraYoheiMaeshimaDahongWangNoriyoshiMasuokaKeikiOginoHirofumiMakinoBackground: Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model.
Methods: ADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups.
Results: The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation.
Conclusions: These data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0303-720734812012Peroxisome proliferator-activated receptor activity is involved in the osteoblastic differentiation regulated by bone morphogenetic proteins and tumor necrosis factor-α.224232ENMarikoTakanoOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciFumioOtsukaOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciYoshinoriMatsumotoOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciKenichiInagakiOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciMasayaTakedaOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciEriNakamuraOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciNaokoTsukamotoOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciTomokoMiyoshiOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciKen-eiSadaOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciHirofumiMakinoOkayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Med & Clin SciRecent studies have suggested possible adverse effects of thiazolidinediones on bone metabolism. However, the detailed mechanism by which the activity of PPAR affects bone formation has not been elucidated. Impaired osteoblastic function due to cytokines is critical for the progression of inflammatory bone diseases. In the present study, we investigated the cellular mechanism by which PPAR actions interact with osteoblast differentiation regulated by BMP and TNF-alpha using mouse myoblastic C2C12 cells. BMP-2 and -4 potently induced the expression of various bone differentiation markers including Runx2, osteocalcin, type-1 collagen and alkaline phosphatase (ALP) in C2C12 cells. When administered in combination with a PPAR alpha agonist (fenofibric acid) but not with a PPAR gamma agonist (pioglitazone), BMP-4 enhanced osteoblast differentiation through the activity of PPAR alpha. The osteoblastic changes induced by BMP-4 were readily suppressed by treatment with TNF-alpha. Interestingly, the activities of PPAR alpha and PPAR gamma agonists reversed the suppression by TNF-alpha of osteoblast differentiation induced by BMP-4. Furthermore, TNF-alpha-induced phosphorylation of MAPKs, NF kappa B, I kappa B and Stat pathways was inhibited in the presence of PPAR alpha and PPAR gamma agonists with reducing TNF-alpha receptor expression. In view of the finding that inhibition of SAPK/JNK. Stat and NF kappa B pathways reversed the TNF-alpha suppression of osteoblast differentiation, we conclude that these cascades are functionally involved in the actions of PPARs that antagonize TNF-alpha-induced suppression of osteoblast differentiation. It was further discovered that the PPAR alpha agonist enhanced BMP-4-induced Smad1/5/8 signaling through downregulation of inhibitory Smad6/7 expression, whereas the PPAR gamma agonist impaired this activity by suppressing BMPRII expression. On the other hand, BMPs increased the expression levels of PPAR alpha and PPAR gamma in the process of osteoblast differentiation. Thus, PPAR alpha actions promote BMP-induced osteoblast differentiation, while both activities of PPAR alpha and PPAR gamma suppress TNF-alpha actions. Collectively, our present data establishes that PPAR activities are functionally involved in modulating the interaction between the BMP system and TNF-alpha receptor signaling that is crucial for bone metabolism.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6662012Losartan/Hydrochlorothiazide Combination Therapy Surpasses High-dose Angiotensin Receptor Blocker in the Reduction of Morning Home Blood Pressure in Patients with Morning Hypertension449459ENYoshihisaHanayamaHaruhito AdamUchidaYoshioNakamuraHirofumiMakinoOriginal Article10.18926/AMO/49041Angiotensin receptor blockers (ARBs) are the first-line antihypertensive agents. In clinical practice, it is often difficult to achieve the recommended blood pressure level by ARBs in their ordinal dosages alone. This study examined the practical efficacy of a combination therapy of ARB with thiazide diuretics for lowering morning home blood pressure (MHBP) in comparison to high-dose ARB therapy in patients with morning hypertension administered an ordinal dosage of ARB. This study was performed in a prospective, randomized, open-labeled and blind-endpoint fashion. Patients were considered to have morning hypertension when their self-measured systolic MHBPs were 135mmHg or higher, irrespective of their diastolic MHBP and office blood pressures (OBPs). Forty-eight outpatients with morning hypertension receiving the ordinal dosage of ARB were given either losartan/hydrochlorothiazide (n＝26) or high-dose ARB (n＝22) in place of their previously prescribed ARB. No change in any medication was permitted during this period. Decreases of both systolic and diastolic MHBP after 3 months of treatment were significantly greater in the losartan/hydrochlorothiazide group than in the high-dose ARB group (p＜0.05, respectively). The ratio of adverse events was somewhat high (23.1% in the losartan/hydrochlorothiazide group, 9.1% in the high-dose ARB group, respectively). However, there were no significant differences in any particular adverse event between groups. This study suggested losartan/hydrochlorothiazide might be superior to high-dose ARB for reducing morning home blood pressure.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812422012RXR阻害によるp53-p21<sup>Cip1</sup>経路の活性化およびG0/G1細胞周期停止を介した抗肥満作用97100ENAtsukoNakatsukaJunWadaHirofumiMakinoNo potential conflict of interest relevant to this article was reported.