Department of Diabetology and Endocrinology, Kanazawa Medical University, Ishikawa, Japan.
Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
Aging (Albany NY). 2020 Jun 7;12(12):11325-11336. doi: 10.18632/aging.103410.
Mitochondrial oxidative stress is a significant contributor to the pathogenesis of diabetic kidney disease (DKD). We previously showed that mitochondrial oxidative stress in the kidneys of Zucker diabetic fatty rats is associated with a decreased intracellular NAD/NADH ratio and NAD-dependent deacetylase Sirt3 activity, and increased expression of the NAD-degrading enzyme CD38. In this study, we used a CD38 inhibitor, apigenin, to investigate the role of CD38 in DKD. Apigenin significantly reduced renal injuries, including tubulointerstitial fibrosis, tubular cell damage, and pro-inflammatory gene expression in diabetic rats. In addition, apigenin down-regulated CD38 expression, and increased the intracellular NAD/NADH ratio and Sirt3-mediated mitochondrial antioxidative enzyme activity in the kidneys of diabetic rats. , inhibition of CD38 activity by apigenin or CD38 knockdown increased the NAD/NADH ratio and Sirt3 activity in renal proximal tubular HK-2 cells cultured under high-glucose conditions. Together, these results demonstrate that by inhibiting the Sirt3 activity and increasing mitochondrial oxidative stress in renal tubular cells, CD38 plays a crucial role in the pathogenesis of DKD.
线粒体氧化应激是糖尿病肾病（DKD）发病机制的重要因素。我们之前的研究表明，糖尿病肥胖 Zucker 大鼠肾脏中的线粒体氧化应激与细胞内 NAD/NADH 比例降低和 NAD 依赖性去乙酰化酶 Sirt3 活性以及 NAD 降解酶 CD38 的表达增加有关。在这项研究中，我们使用了 CD38 抑制剂白杨素来研究 CD38 在 DKD 中的作用。白杨素可显著减轻糖尿病大鼠的肾脏损伤，包括肾小管间质纤维化、肾小管细胞损伤和促炎基因表达。此外，白杨素下调了糖尿病大鼠肾脏中的 CD38 表达，增加了细胞内 NAD/NADH 比例和 Sirt3 介导的线粒体抗氧化酶活性。在高糖培养条件下，白杨素抑制 CD38 活性或敲低 CD38 可增加肾近端小管 HK-2 细胞中的 NAD/NADH 比例和 Sirt3 活性。综上所述，这些结果表明，CD38 通过抑制 Sirt3 活性和增加肾小管细胞中的线粒体氧化应激，在 DKD 的发病机制中发挥关键作用。
