Diabetic kidney disease (DKD) is a major cause of end-stage renal disease worldwide. Although the detailed pathogenesis of DKD is not elucidated yet, aging is recognized as one of the risk factors for the development of end-stage renal failure due to chronic kidney disease including DKD. Therefore, investigation of aging-related mechanism would be a novel therapeutic target for DKD. NAD levels decrease during aging. Previous report demonstrated that expression and activity of the CD38 (NADase) increased with aging, and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of Sirt3 activity. However, the role of CD38 in the pathogenesis for DKD has never been investigated. In this study, we evaluated the role of CD38 on the mechanisms of renal mitochondrial oxidative stress which is related to changing Sirt3 activity, in Zucker Diabetic Fatty rats (ZDFRs) and in cultured HK2 cells under high-glucose condition. At 28 weeks of age, the ZDFRs exhibited elevated HbA1c levels, heavier kidney weight, increased urinary albumin, L-FABP and 8-OHdG excretion, histological tubulo-interstitial fibrosis and tubular cell damage, compared to nondiabetic Zucker Lean rats. Additionally, in renal mitochondria, the NAD+/NADH ratio was reduced, and acetylation levels of mitochondrial antioxidant enzymes, IDH2 and SOD2, which are regulated by Sirt3, were increased in ZDFRs. Similarly, in cultured HK2 cells under high-glucose condition, CD38 expression was increased, resulting in the reduction of NAD+/NADH ratio and Sirt3 activity, which increased in acetylation levels of IDH2 and SOD2. Administration of the CD38 inhibitor, apigenin, to ZDFRs and HK2 cells, restored the NAD+/NADH ratio, decreased the levels of IDH2 and SOD2 acetylation. Therefore, restoring Sirt3 activation by suppression of CD38 may be a novel therapeutic target for DKD.
Y. Ogura: None. M. Kitada: Research Support; Self; Astellas Pharma US, Inc., Kyowa Hakko Kirin Co., Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., Boehringer Ingelheim GmbH, Taisho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. I. Monno: None. A. Watanabe: None. D. Koya: None.