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.

中文翻译：

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糖尿病肾病发病机理的新见解：近端肾小管是糖尿病肾氧化应激的主要靶标。

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，人们公认糖尿病肾病的主要特征是肾小球缺陷，而临床观察表明，在肾病早期，肾小管损害与肾功能障碍密切相关。在这项研究中，我们使用链脲佐菌素（STZ）诱导的糖尿病小鼠模型对早期糖尿病肾中的肾小管病变进行了病理组织学分析。结果显示，在早期糖尿病肾脏中，肾小管的组织学改变最初表现为液泡状核酸结构，PAS阳性物质的积累和加速的恢复压力，而肾小球病变不存在，并且这些肾小管缺陷主要位于近端肾小管。此外，在受损的糖尿病近端肾小管中也观察到RAGE的表达增强，表明AGEs-RAGE信号通路异常激活，并且通过受损的自噬/溶酶体系统，氧化修饰的线粒体积累。我们的研究结果表明，近端肾小管缺损是与糖尿病肾病进展日益相关的初始病理事件，控制肾小管损伤可能是糖尿病性肾病临床治疗的有效治疗策略。在受损的糖尿病近端肾小管中也观察到通过受损的自噬/溶酶体系统氧化修饰的线粒体的积累和积累。我们的研究结果表明，近端肾小管缺损是与糖尿病肾病进展日益相关的初始病理事件，控制肾小管损伤可能是糖尿病性肾病临床治疗的有效治疗策略。在受损的糖尿病近端肾小管中也观察到通过受损的自噬/溶酶体系统氧化修饰的线粒体的积累和积累。我们的研究结果表明，近端肾小管缺损是与糖尿病肾病进展日益相关的初始病理事件，控制肾小管损伤可能是糖尿病性肾病临床治疗的有效治疗策略。