a Department of Diabetology and Endocrinology , Kanazawa Medical University , Ishikawa , Japan.
b Division of Anticipatory Molecular Food Science and Technology , Medical Research Institute, Kanazawa Medical University , Ishikawa , Japan.
Redox Rep. 2018 Dec;23(1):153-159. doi: 10.1080/13510002.2018.1487174.
Mitochondrial oxidative stress is involved in the pathogenesis of diabetic kidney disease. The objective of our study is to identify the mechanisms of renal mitochondrial oxidative stress, focusing on Sirt3, which is nicotinamide adenine dinucleotide (NAD; oxidized NAD)-dependent deacetylase in mitochondria.
Renal mitochondrial oxidative stress and Sirt3 activity, using Zucker diabetic fatty rats (ZDFRs) and cultured proximal tubular cells under high-glucose condition were evaluated.
At 28 weeks of age, ZDFRs exhibited the increased urinary albumin/liver-type fatty acid-binding protein (L-FABP)/8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion, histological tubular cell damage, compared to non-diabetic Zucker Lean rats. In renal mitochondria, acetylated isocitrate dehydrogenase2 (IDH2) and superoxide dismutase2 (SOD2), accompanied with mitochondrial oxidative stress and mitochondrial morphologic alterations, were increased in ZDFRs, indicating inactivation of Sirt3. Additionally, expression of the NAD-degrading enzyme, CD38, was increased, and the NAD/NADH (reduced NAD) ratio was reduced in the renal cortex of ZDFRs. High-glucose stimulation in cultured proximal tubular cells also resulted in an increase in acetylated IDH2/SOD2, CD38 overexpression and a reduction in the NAD/NADH ratio.
Enhancement of mitochondrial oxidative stress in the diabetic kidney was mediated by the reduction of Sirt3 activity. CD38 overexpression may be related to a reduction in the NAD/NADH ratio in the diabetic kidney.
线粒体氧化应激与糖尿病肾病的发病机制有关。本研究旨在确定肾脏线粒体氧化应激的机制，重点研究 Sirt3，它是烟酰胺腺嘌呤二核苷酸（NAD；氧化型 NAD）依赖的线粒体中的去乙酰化酶。
使用 Zucker 糖尿病肥胖大鼠（ZDFR）和高糖条件下培养的近端肾小管细胞评估肾脏线粒体氧化应激和 Sirt3 活性。
28 周龄时，ZDFR 与非糖尿病 Zucker 瘦鼠相比，尿白蛋白/肝型脂肪酸结合蛋白（L-FABP）/8-羟基-2'-脱氧鸟苷（8-OHdG）排泄、组织学肾小管细胞损伤增加。在肾脏线粒体中，乙酰化异柠檬酸脱氢酶 2（IDH2）和超氧化物歧化酶 2（SOD2）增加，伴随着线粒体氧化应激和线粒体形态改变，表明 Sirt3 失活。此外，NAD 降解酶 CD38 的表达增加，ZDFR 肾皮质中的 NAD/NADH（还原型 NAD）比值降低。高糖刺激培养的近端肾小管细胞也导致乙酰化 IDH2/SOD2、CD38 过表达增加和 NAD/NADH 比值降低。
糖尿病肾脏中线粒体氧化应激的增强是由 Sirt3 活性降低介导的。CD38 的过表达可能与糖尿病肾脏中 NAD/NADH 比值降低有关。
