Springer Science and Business Media LLC Acta Medica Okayama 2045-2322 15 1 2025 Role of galectin-9 in the development of gestational diabetes mellitus 18981 EN Haya Hamed Hassan Albuayjan Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mayu Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ryosuke Sugawara Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Eri Katsuyama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Koki Mise Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yukiko Oi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ayaka Kanno Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University BoXuan Yang Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshihisa Tahara Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ichiro Nojima Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jota Maki Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Eriko Eto Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kei Hayata Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hisashi Masuyama Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Galectin-9 (Gal-9) is highly expressed in trophoblasts in placenta. Interaction between Gal-9 and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) is important for the differentiation of tissue resident natural killer (trNK) cells in placenta and maintenance of normal pregnancy. Furthermore, the enhanced maternal systemic inflammation associated with increased proinflammatory cytokines in preeclampsia is mediated by enhanced interaction between Gal-9 and Tim-3. However, the role of Gal-9 in gestational diabetes (GDM) remains unexplored. Plasma Gal-9 levels were elevated at 3rd trimester in pregnant women with GDM and positively correlated with placenta and newborn weight. Lgals9 knockout pregnant mice fed with high fat diet (HFD KO) demonstrated maternal glucose intolerance and fetus macrosomia compared with controls (HFD WT). In HFD KO, increased proliferating cells, reduced apoptosis, and autophagy impairment were observed in junctional zones. The number of trNK cells and percentage of Tim-3 + trNK increased, while early apoptosis percentage in Tim-3 + trNK was reduced in placenta of HFD KO. The elevation of plasma Gal-9 may be a biomarker for prediction of maternal glucose intolerance and fetal macrosomia in pregnant women with GDM and Gal-9 functions as a compensation factor for GDM by inducing apoptosis in Tim-3 + trNK cells. No potential conflict of interest relevant to this article was reported.

American Diabetes Association Acta Medica Okayama 0012-1797 73 5 2024 GRP78 Contributes to the Beneficial Effects of SGLT2 Inhibitor on Proximal Tubular Cells in DKD 763 779 EN Atsuko Nakatsuka Division of Kidney, Diabetes and Endocrine Diseases, Okayama University Hospital Satoshi Yamaguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-β1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-β1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-β1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-β1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection. No potential conflict of interest relevant to this article was reported.

BMJ Publishing Group Acta Medica Okayama 2052-4897 12 3 2024 Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3) e004237 EN Asami Ueno Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Yasuhiro Onishi Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Koki Mise Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Satoshi Yamaguchi Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Ayaka Kanno Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Ichiro Nojima Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Chigusa Higuchi Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Haruhito A. Uchida Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Kenichi Shikata Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Satoshi Miyamoto Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Atsuko Nakatsuka Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Jun Eguchi Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Kazuyuki Hida Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center Akihiro Katayama Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center Mayu Watanabe Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center Tatsuaki Nakato Department of Internal Medicine, Okayama Saiseikai General Hospital Atsuhito Tone Department of Internal Medicine, Okayama Saiseikai General Hospital Sanae Teshigawara Okayama Saiseikai General Hospital Takashi Matsuoka Department of Diabetic Medicine, Kurashiki Central Hospital Shinji Kamei Department of Diabetic Medicine, Kurashiki Central Hospital Kazutoshi Murakami Department of Diabetic Medicine, Kurashiki Central Hospital Ikki Shimizu Sakakibara Heart Institute of Okayama Katsuhito Miyashita Japanese Red Cross Okayama Hospital Shinichiro Ando Okayama City General Medical Center Tomokazu Nunoue Nunoue Clinic Jun Wada Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Introduction ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. Research design and methods Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. Results The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. Conclusions Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD.Trial registration number UMIN000011525. No potential conflict of interest relevant to this article was reported.

Ovid Technologies (Wolters Kluwer Health) Acta Medica Okayama 2641-7650 5 2 2023 Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes 182 194 EN Yuzuki Kano Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Satoshi Yamaguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Koki Mise Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Chieko Kawakita Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yasuhiro Onishi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Naoko Kurooka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ryosuke Sugawara Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Haya Hamed Hassan Albuayjan Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background Inhibition of glucose influx into proximal tubular cells (PTCs) by sodium–glucose cotransporter 2 inhibitors revealed prominent therapeutic effects on diabetic kidney disease. Collectrin (CLTRN) serves as a chaperone for the trafficking of neutral amino acid (AA) transporters in the apical membranes of PTCs. We investigated the beneficial effects of reduced influx of AAs into PTCs in diabetes and obesity model of Cltrn−/y mice. Methods Cltrn+/y and Cltrn−/y mice at age 5 weeks were assigned to standard diet and streptozotocin and high-fat diet (STZ-HFD)–treated groups. Results At age 22–23 weeks, body weight and HbA1c levels significantly increased in STZ-HFD-Cltrn+/y compared with standard diet-Cltrn+/y; however, they were not altered in STZ-HFD-Cltrn−/y compared with STZ-HFD-Cltrn+/y. At age 20 weeks, urinary albumin creatinine ratio was significantly reduced in STZ-HFD-Cltrn−/y compared with STZ-HFD-Cltrn+/y. Under the treatments with STZ and HFD, the Cltrn gene deficiency caused significant increase in urinary concentration of AAs such as Gln, His, Gly, Thr, Tyr, Val, Trp, Phe, Ile, Leu, and Pro. In PTCs in STZ-HFD-Cltrn+/y, the enlarged lysosomes with diameter of 10 μm or more were associated with reduced autolysosomes, and the formation of giant lysosomes was prominently suppressed in STZ-HFD-Cltrn−/y. Phospho-mTOR and inactive form of phospho-transcription factor EB were reduced in STZ-HFD-Cltrn−/y compared with STZ-HFD-Cltrn+/y. Conclusions The reduction of AAs influx into PTCs inactivated mTOR, activated transcription factor EB, improved lysosome function, and ameliorated vacuolar formation of PTCs in STZ-HFD-Cltrn−/y mice. No potential conflict of interest relevant to this article was reported.

Frontiers Media SA Acta Medica Okayama 1664-2392 12 2022 Adipocyte-Specific Inhibition of Mir221/222 Ameliorates Diet-Induced Obesity Through Targeting Ddit4 750261 EN Satoshi Yamaguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Dongxiao Zhang Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Katayama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Naoko Kurooka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryosuke Sugawara Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Haya Hamed Hassan Albuayjan Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences MicroRNAs expressed in adipocytes are involved in transcriptional regulation of target mRNAs in obesity, but miRNAs critically involved in this process is not well characterized. Here, we identified upregulation of miR-221-3p and miR-222-3p in the white adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir221 and Mir222 are paralogous genes and share the common seed sequence and Mir221/222AdipoKO mice fed with HFHS chow demonstrated resistance to the development of obesity compared with Mir221/222(flox/y). Ddit4 is a direct target of Mir221 and Mir222, and the upregulation of Ddit4 in Mir221/222AdipoKO was associated with the suppression of TSC2 (tuberous sclerosis complex 2)/mammalian target of rapamycin complex 1 (mTORC1)/S6K (ribosomal protein S6 kinase) pathway. The overexpression of miR-222-3p linked to enhanced adipogenesis, and it may be a potential candidate for miRNA-based therapy. No potential conflict of interest relevant to this article was reported.

Frontiers Media SA Acta Medica Okayama 2297-055X 8 2021 Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2) 668059 EN Koki Mise Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mariko Imamura Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Yamaguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mayu Watanabe Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Chigusa Higuchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Katayama Diabetes Center, Okayama University Hospital Satoshi Miyamoto Center for Innovative Clinical Medicine, Okayama University Hospital Haruhito A. Uchida Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuyuki Hida Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center Tatsuaki Nakato Okayama Saiseikai General Hospital Atsuhito Tone Okayama Saiseikai General Hospital Sanae Teshigawara Okayama Saiseikai General Hospital Takashi Matsuoka Kurashiki Central Hospital Shinji Kamei Kurashiki Central Hospital Kazutoshi Murakami Kurashiki Central Hospital Ikki Shimizu The Sakakibara Heart Institute of Okayama Katsuhiro Miyashita Japanese Red Cross Okayama Hospital Shinichiro Ando Okayama City General Medical Center Tomokazu Nunoue Nunoue Clinic Michihiro Yoshida Center for Innovative Clinical Medicine, Okayama University Hospital Masao Yamada GlycoTechnica Ltd. Kenichi Shikata Center for Innovative Clinical Medicine, Okayama University Hospital Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background: Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear. Methods: Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease. Results: During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24-2.55, P = 0.002) and Calsepa [High-Man (Man2-6)]: 1.56 (1.19-2.04, P = 0.001). Common glycan binding to these lectins was high-mannose type of N-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001-0.055, P = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045-0.692, P = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively]. Conclusion: The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal N-glycosylation occurring in patients with diabetes at higher risk of CVE. No potential conflict of interest relevant to this article was reported.

Nature Acta Medica Okayama 2045-2322 11 1 2021 Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2 5991 EN Tomokazu Nunoue Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Yamaguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Sanae Teshigawara Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Katayama Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiro Niki Department of Immunology, Kagawa University Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences The adipose tissue is regarded as an endocrine organ and secretes bioactive adipokines modulating chronic inflammation and oxidative stress in obesity. Gal-9 is secreted out upon cell injuries, interacts with T-cell immunoglobulin-3 (Tim-3) and induces apoptosis in activated Th1 cells. Gal-9 also binds to protein disulfide isomerase (PDI), maintains PDI on surface of T cells, and increases free thiols in the disulfide/thiol cycles. To explore the molecular mechanism of obesity, we investigated Gal-9(-/-) and Gal-9(wt/wt) C57BL/6J mice fed with high fat-high sucrose (HFHS) chow. Gal-9(-/-) mice were resistant to diet-induced obesity associated with reduction of epididymal and mesenteric fat tissues and improved glucose tolerance compared with Gal-9(wt/wt) mice. However, the number of M1, M2 macrophages, and M1/M2 ratio in epididymal fat were unaltered. Under HFHS chow, Gal-9(-/-) mice receiving Gal-9(-/-) or Gal-9(wt/wt) bone marrow-derived cells (BMCs) demonstrated significantly lower body weight compared with Gal-9(wt/wt) mice receiving Gal-9(-/-) BMCs. We identified the binding between Gal-9 and peroxiredoxin-2 (PRDX2) in sugar chain-independent manner by nanoLC-MS/MS, immunoprecipitation, and pull-down assay. In 3T3L1 adipocytes, Gal-9 knockdown shifts PRDX2 monomer (reduced form) dominant from PRDX2 dimer (oxidized form) under oxidative stress with H2O2. The inhibition of Gal-9 in adipocytes may be a new therapeutic approach targeting the oxidative stress and subsequent glucose intolerance in obesity. No potential conflict of interest relevant to this article was reported.

Nature Acta Medica Okayama 2399-3642 4 1 2021 A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease 373 EN Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Yamaguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shigeru Kakuta Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, the University of Tokyo Yoichiro Iwakura Research Institute for Biomedical Sciences, Tokyo University of Science Hitoshi Sugiyama Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin-/- obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD. No potential conflict of interest relevant to this article was reported.

Nature Research Acta Medica Okayama 2045-2322 10 1 2020 Dysfunction of CD8+PD-1+T cells in type 2 diabetes caused by the impairment of metabolism-immune axis 14928 EN Ichiro Nojima Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shingo Eikawa Department of Hematology/Oncology, Hess Cancer Institute, Icahn School of Medicine At Mount Sinai Nahoko Tomonobu Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshiko Hada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Nobuo Kajitani Department of Internal Medicine, Diabetes Center, Okayama City Hospital Sanae Teshigawara Diabetes Center, Okayama S Satoshi Miyamoto Center for Innovative Clinical Medicine, Okayama University Hospital Atsuhito Tone Diabetes Center, Okayama Saiseikai General Hospital Haruhito A. Uchida Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kenichi Shikata Center for Innovative Clinical Medicine, Okayama University Hospital Heiichiro Udono Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences The metabolic changes and dysfunction in CD8+T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8+splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8+splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8+PD-1+T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8+PD-1+T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity. No potential conflict of interest relevant to this article was reported.

Springer Acta Medica Okayama 2190-1678 11 2 2019 The hypoglycemia-prevention effect of sensor-augmented pump therapy with predictive low glucose management in Japanese patients with type 1 diabetes mellitus: a short-term study 97 104 EN Akihiro Katayama Diabetes Center, Okayama University Hospital Atsuhito Tone Diabetes Center, Okayama Saiseikai General Hospital Mayu Watanabe Department of Primary Care and Medical Education, Okayama University Sanae Teshigawara Diabetes Center, Okayama Saiseikai General Hospital Satoshi Miyamoto Center for Innovative Clinical Medicine, Okayama University Hospital Jun Eguchi Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Nakatsuka Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci Kenichi Shikata Center for Innovative Clinical Medicine, Okayama University Hospital Jun Wada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Aims/introduction The predictive low glucose management (PLGM) system was introduced in March 2018 in Japan. Although there are some reports demonstrating the benefit of PLGM in preventing hypoglycemia, no data are currently available in Japanese patients with type 1 diabetes mellitus (T1DM). The aim of the present study is to evaluate the effect of PLGM with sensor-augmented pump therapy in the prevention of hypoglycemia in Japanese patients. Materials and methods We included 16 patients with T1DM who used the MiniMed®640G system after switching from the MiniMed®620G system. We retrospectively analysed the data of the continuous glucose monitoring system in 1 month after switching to MiniMed®640G. Results The area under the curve (AUC) of hypoglycemia of < 70 mg/dL was lowered from 0.42 ± 0.43 mg/dL day to 0.18 ± 0.18 mg/dL day (P = 0.012). Correspondingly, the duration of severe hypoglycemia (< 54 mg/dL) was reduced significantly from 15.3 ± 21.7 min/day to 4.8 ± 6.9 min/day (P = 0.019). The duration of hypoglycemia was reduced, but the reduction was not significant. Regarding the AUC for hyperglycemia > 180 mg/dL and the duration of hyperglycemia did not change. With the PLGM function, 79.3% of the predicted hypoglycemic events were avoided. Conclusions The hypoglycemia avoidance rate was comparable to those in previous reports. In addition, we demonstrated that PLGM can markedly suppress severe hypoglycemia without deteriorating glycemic control in Japanese T1DM patients. It is necessary to further investigate the effective use of the PLGM feature such as establishing a lower limit and the timing of resumption. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 3 2016 Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes 151 158 EN Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Atsuko Nakatsuka Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Review 10.18926/AMO/54413 The mitochondria are involved in active and dynamic processes, such as mitochondrial biogenesis, fission, fusion and mitophagy to maintain mitochondrial and cellular functions. In obesity and type 2 diabetes, impaired oxidation, reduced mitochondrial contents, lowered rates of oxidative phosphorylation and excessive reactive oxygen species (ROS) production have been reported. Mitochondrial biogenesis is regulated by various transcription factors such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs). Mitochondrial fusion is promoted by mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1), while fission is governed by the recruitment of dynamin-related protein 1 (DRP1) by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51), and fission 1 (FIS1). Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARKIN promote DRP1-dependent mitochondrial fission, and the outer mitochondrial adaptor MiD51 is required in DRP1 recruitment and PARKIN-dependent mitophagy. This review describes the molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy. No potential conflict of interest relevant to this article was reported.

PUBLIC LIBRARY SCIENCE Acta Medica Okayama 1932-6203 9 3 2014 Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy e92647 EN Mayu Watanabe Atsuko Nakatsuka Kazutoshi Murakami Kentaro Inoue Takahiro Terami Chigusa Higuchi Akihiro Katayama Sanae Teshigawara Jun Eguchi Daisuke Ogawa Eijiro Watanabe Jun Wada Hirofumi Makino Phosphatidylethanolamine 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 SCIENCE Acta Medica Okayama 1932-6203 9 1 2014 Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines e85594 EN Daisuke Ogawa Jun Eguchi Jun Wada Naoto Terami Takashi Hatanaka Hiromi Tachibana Atsuko Nakatsuka Chikage Sato Horiguchi Naoko Nishii Hirofumi Makino Nuclear 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 Group Acta Medica Okayama 2045-2322 6 2016 Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis 21721 EN Atsuko Nakatsuka Makoto Matsuyama Satoshi Yamaguchi Akihiro Katayama Jun Eguchi Kazutoshi Murakami Sanae Teshigawara Daisuke Ogawa Nozomu Wada Tetsuya Yasunaka Fusao Ikeda Akinobu Takaki Eijiro Watanabe Jun Wada 　Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt−/− mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt−/− mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities. No potential conflict of interest relevant to this article was reported.

Nature Publishing Group Acta Medica Okayama 2045-2322 5 2015 Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis 16920 EN Akihiro Katayama Atsuko Nakatsuka Jun Eguchi Kazutoshi Murakami Sanae Teshigawara Motoko Kanzaki Tomokazu Nunoue Kazuyuki Hida Nozomu Wada Tetsuya Yasunaka Fusao Ikeda Akinobu Takaki Kazuhide Yamamoto Hiroshi Kiyonari Hirofumi Makino Jun Wada Nonalcoholic 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.

Acta Medica Okayama 6 2013 Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes 233 240 EN Takahiro Terami Jun Wada Kentaro Inoue Atsuko Nakatsuka Daisuke Ogawa Sanae Teshigawara Kazutoshi Murakami Akihiro Katayama Jun Eguchi Hirofumi Makino Purpose: 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 Science Acta Medica Okayama 1932-6203 8 10 2013 Urinary Fetuin-A Is a Novel Marker for Diabetic Nephropathy in Type 2 Diabetes Identified by Lectin Microarray EN Kentaro Inoue Jun Wada Jun Eguchi Atsuko Nakatsuka Sanae Teshigawara Kazutoshi Murakami Daisuke Ogawa Takahiro Terami Akihiro Katayama Atsuhito Tone Izumi Iseda Kazuyuki Hida Masao Yamada Tomohisa Ogawa Hirofumi Makino We 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.

岡山医学会 Acta Medica Okayama 0030-1558 126 2 2014 平成25年度岡山医学会賞胸部・循環研究奨励賞（砂田賞） 95 98 EN Atsuko Nakatsuka No potential conflict of interest relevant to this article was reported.

Biomed Central Ltd Acta Medica Okayama 1471-2369 14 2013 Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease EN Yuko Kurose Jun Wada Motoko Kanzaki Sanae Teshigawara Atsuko Nakatsuka Kazutoshi Murakami Kentaro Inoue Takahiro Terami Akihiro Katayama Mayu Watanabe Chigusa Higuchi Jun Eguchi Nobuyuki Miyatake Hirofumi Makino Background: 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.

Biomed Central Ltd Acta Medica Okayama 1471-2369 13 2012 The serum vaspin levels are reduced in Japanese chronic hemodialysis patients EN Junko Inoue Jun Wada Sanae Teshigawara Kazuyuki Hida Atsuko Nakatsuka Yuji Takatori Shoichirou Kojo Shigeru Akagi Kazushi Nakao Nobuyuki Miyatake John F. McDonald Hirofumi Makino Background: 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 School Acta Medica Okayama 0386-300X 67 3 2013 Cell Cycle Abnormality in Metabolic Syndrome and Nuclear Receptors as an Emerging Therapeutic Target 129 134 EN Atsuko Nakatsuka Jun Wada Hirofumi Makino Review 10.18926/AMO/50405 In 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 Okayama 0012-1797 61 11 2012 Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex 2823 2832 EN Atsuko Nakatsuka Jun Wada Izumi Iseda Sanae Teshigawara Kanji Higashio Kazutoshi Murakami Motoko Kanzaki Kentaro Inoue Takahiro Terami Akihiro Katayama Kazuyuki Hida Jun Eguchi Chikage Sato Horiguchi Daisuke Ogawa Yasushi Matsuki Ryuji Hiramatsu Hideo Yagita Shigeru Kakuta Yoichiro Iwakura Hirofumi Makino It 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, 2012 No potential conflict of interest relevant to this article was reported.