New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney
New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney
复制标题
糖尿病肾病发病机制的新见解：近端肾小管是糖尿病肾脏氧化应激的主要靶点
DOI：
10.1267/ahc.20008
复制
发表时间：
2020-01-01
影响因子：
2.4
通讯作者：
Kitazawa, Sohei
中科院分区：
文献类型：
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作者：
Haraguchi, Ryuma;Kohara, Yukihiro;Kitazawa, Sohei
糖尿病肾病是终末期肾衰竭的主要来源，影响约三分之一的糖尿病病例。长期以来，人们一直认为糖尿病肾病的主要特征是肾小球缺陷，而临床观察表明，在糖尿病肾病的早期阶段，肾小管损伤与肾功能障碍密切相关。在这项研究中，我们进行了病理组织学分析，重点是肾小管病变的早期阶段糖尿病肾使用链脲佐菌素（STZ）诱导的糖尿病小鼠模型。结果表明，肾小管的组织学改变，空泡状的核结构，PAS阳性物质的积累，和加速恢复应力，发生最初没有肾小球病变的存在下，在早期阶段的糖尿病肾脏，这些肾小管缺陷主要局限于近端肾小管。此外，在受损的糖尿病近端肾小管中也观察到增强的AGEs表达，表明AGEs-β信号通路的异常激活，以及通过受损的自噬/溶酶体系统的氧化修饰的线粒体的积累。我们的研究结果表明，近端肾小管缺损是糖尿病肾病进展的初始病理事件，控制肾小管损伤可能是临床治疗糖尿病肾病的有效治疗策略。
Diabetic nephropathy is a major source of end-stage renal failure, affecting about one-third cases of diabetes mellitus. It has long been accepted that diabetic nephropathy is mainly characterized by glomerular defects, while clinical observations have implied that renal tubular damage is closely linked to kidney dysfunction at the early stages of diabetic nephropathy. In this study, we conducted pathohistological analyses focusing on renal tubular lesions in the early-stage diabetic kidney with the use of a streptozotocin (STZ)-induced diabetes mellitus mouse model. The results revealed that histological alterations in renal tubules, shown by a vacuolar nucleic structure, accumulations of PAS-positive substance, and accelerated restoration stress, occur initially without the presence of glomerular lesions in the early-stage diabetic kidney, and that these tubular defects are localized mainly in proximal renal tubules. Moreover, enhanced expression of RAGE, suggesting an aberrant activation of AGEs-RAGE signaling pathway, and accumulation of oxidative modified mitochondria through the impaired autophagy/lysosome system, were also seen in the damaged diabetic proximal renal tubules. Our findings indicate that proximal tubular defects are the initial pathological events increasingly linked to the progression of diabetic nephropathy, and that controlling renal tubular damage could be an effective therapeutic strategy for the clinical treatment of diabetic nephropathy.