Wiley Acta Medica Okayama 2040-1116 14 2 2022 Suramin prevents the development of diabetic kidney disease by inhibiting NLRP3 inflammasome activation in KK-Ay mice 205 220 EN Kaori Oda Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Satoshi Miyamoto Center for Innovative Clinical Medicine, Okayama University Hospital Ryo Kodera Osafune Clinic Jun Wada Department of Nephrology, Rheumatology, Endocrinology and Metabolism Kenichi Shikata Center for Innovative Clinical Medicine, Okayama University Hospital Aims/Introduction Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL-18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg-A(y)/TaJcl (KK-Ay) mice against DKD progression. Materials and Methods Suramin or saline was administered i.p. to KK-Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin. Results Suramin treatment significantly suppressed the increase in the urinary albumin-to-creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs. Conclusions These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2040-1116 11 2 2020 Prevalence of albuminuria and renal dysfunction, and related clinical factors in Japanese patients with diabetes: The Japan Diabetes Complication and its Prevention prospective study 5 325 332 EN Kenichi Shikata Center for Innovative Clinical Medicine, Okayama University Hospital Ryo Kodera The Japan Diabetes Society Kazunori Utsunomiya The Japan Diabetes Society Daisuke Koya The Japan Diabetes Society Rimei Nishimura The Japan Diabetes Society Satoshi Miyamoto Center for Innovative Clinical Medicine, Okayama University Hospital Naoko Tajima The Japan Diabetes Society the JDCP study group Aims/Introduction</br> To clarify the prevalence of albuminuria and renal dysfunction, and related factors in Japanese patients with diabetes, we analyzed the baseline data of the Japan Diabetes Complication and its Prevention prospective study.</br> Materials and Methods</br> We used the data of 355 patients with type 1 diabetes and 5,194 patients with type 2 diabetes to evaluate the prevalence of albuminuria and renal dysfunction, and related factors. A binomial logistic regression analysis was used to investigate independent contributing factors for estimated glomerular filtration rate <60 mL/min/1.73 m2 or albuminuria. </br> Results</br> The prevalence of microalbuminuria and macroalbuminuria was 15.2% (54/355) and 3.1% (11/355) in type 1 diabetes patients, and 25.0% (1,298/5,194) and 5.1% (265/5,194) in type 2 diabetes patients, respectively. The proportion of renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2) was 9.9% (35/355) in type 1 diabetes patients, and 15.3% (797/5,194) in type 2 diabetes patients. The proportion of patients with renal dysfunction with normoalbuminuria was 7.3% (26/355) for type 1 diabetes patients, and 9.0% (467/5,194) for type 2 diabetes patients. The factors related to albuminuria in type 2 diabetes patients were glycated hemoglobin, hypertension, age, duration of diabetes, body mass index and estimated glomerular filtration rate. In contrast, factors to related renal dysfunction were age, duration of diabetes, dyslipidemia, hypertension, body mass index, male sex and albuminuria. </br> Conclusions</br> We showed the recent prevalence of albuminuria and renal dysfunction, and related factors in Japanese type 1 and type 2 diabetes patients using the baseline data of the Japan Diabetes Complication and its Prevention prospective study. The current results suggest that renal disease in patients with type 2 diabetes is heterogeneous, and different mechanisms might be involved in albuminuria and deterioration of renal function. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 4 2014 Factors Associated with Remission and/or Regression of Microalbuminuria in Type 2 Diabetes Mellitus 235 241 EN Tetsuichiro Ono Kenichi Shikata Mikako Obika Nobuyuki Miyatake Ryo Kodera Daisyo Hirota Jun Wada Hitomi Kataoka Daisuke Ogawa Hirofumi Makino Original Article 10.18926/AMO/52789 The 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.

岡山医学会 Acta Medica Okayama 0030-1558 126 1 2014 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 1 6 EN Satoshi Miyamoto Kenichi Shikata Kyoko Miyasaka Shinichi Okada Motofumi Sasaki Ryo Kodera Daisho Hirota Nobuo Kajitani Tetsuharu Takatsuka Hitomi Kataoka Usui Shingo Nishishita Chikage Horiguchi Sato Akihiro Funakoshi Hisakazu Nishimori Haruhito Adam Uchida Daisuke Ogawa Hirofumi Makino No potential conflict of interest relevant to this article was reported.

Springer Acta Medica Okayama 1342-1751 16 5 2012 Phenotypic change of macrophages in the progression of diabetic nephropathy; sialoadhesin-positive activated macrophages are increased in diabetic kidney 739 748 EN Ryo Nagase Nobuo Kajitani Kenichi Shikata Daisuke Ogawa Ryo Kodera Shinichi Okada Yuichi Kido Hirofumi Makino Inflammatory 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.