Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy
Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy
复制标题
DOI：
10.1681/asn.2013070810
复制
发表时间：
2014-06-01
影响因子：
13.6
通讯作者：
Jandeleit-Dahm, Karin A.
中科院分区：
文献类型：
--
作者：
Jha, Jay C.;Gray, Stephen P.;Jandeleit-Dahm, Karin A.
糖尿病肾病的发生可能部分是由于肾内氧化应激。NADPH氧化酶包括唯一已知的专用活性氧（ROS）形成酶家族。在啮齿动物肾脏中，表达NADPH氧化酶催化亚基的三种亚型（Nox 1、Nox 2和Nox 4）。在这里，我们表明，Nox 4是在ApoE（-/-）小鼠链脲佐菌素给药诱导的糖尿病肾病小鼠模型中肾脏ROS的主要来源。在链脲佐菌素诱导的糖尿病ApoE（-/-）小鼠中，Nox 4的缺失，而非Nox 1的缺失，导致肾脏保护免于肾小球损伤，如减少的蛋白尿、保留的结构、减少的肾小球细胞外基质蛋白的积聚、减少的肾小球巨噬细胞浸润以及减少的单核细胞趋化蛋白-1和NF-κ B的肾脏表达。重要的是，给予最具特异性的Nox 1/4抑制剂GKT 137831，复制了Nox 4缺失的这些肾保护作用。在人类足细胞中，Nox 4基因的沉默导致ROS的产生减少以及与糖尿病肾病有关的促炎和促纤维化标志物的下调。总的来说，这些结果将Nox 4确定为负责糖尿病肾损伤的ROS的关键来源，并为治疗和/或预防慢性肾衰竭的创新小分子方法提供了原理证明。
Diabetic nephropathy may occur, in part, as a result of intrarenal oxidative stress. NADPH oxidases comprise the only known dedicated reactive oxygen species (ROS)-forming enzyme family. In the rodent kidney, three isoforms of the catalytic subunit of NADPH oxidase are expressed (Nox1, Nox2, and Nox4). Here we show that Nox4 is the main source of renal ROS in a mouse model of diabetic nephropathy induced by streptozotocin administration in ApoE(-/-) mice. Deletion of Nox4, but not of Nox1, resulted in renal protection from glomerular injury as evidenced by attenuated albuminuria, preserved structure, reduced glomerular accumulation of extracellular matrix proteins, attenuated glomerular macrophage infiltration, and reduced renal expression of monocyte chemoattractant protein-1 and NF-kappa B in streptozotocin-induced diabetic ApoE(-/-) mice. Importantly, administration of the most specific Nox1/4 inhibitor, GKT137831, replicated these renoprotective effects of Nox4 deletion. In human podocytes, silencing of the Nox4 gene resulted in reduced production of ROS and downregulation of proinflammatory and profibrotic markers that are implicated in diabetic nephropathy. Collectively, these results identify Nox4 as a key source of ROS responsible for kidney injury in diabetes and provide proof of principle for an innovative small molecule approach to treat and/or prevent chronic kidney failure.