抗衰老基因Klotho及AKT/FoxO信号传导通路在糖尿病肾病中的作用

Diabetes mellitus (DM) is the leading cause of end-stage renal disease (ESRD) worldwide. Despite strict blood glucose, hypertension, and metabolic abnormalities controls, the number of diabetic patients entering ESRD because of DM remains extremely high. Diabetic nephropathy (DN) is a major clinical cause of chronic kidney disease characterized by an increase in urinary protein excretion and progressive decline in renal function. Proteinuria is an important biomarker in DN representing not only early kidney damage but also an independent factor of renal insufficiency. The mechanism account for DN is multifactorial, and there is overwhelming evidence has delineated that renin-angiotensin system, inflammatory cytokines, and transforming growth factor-beta1 have been proposed as important players. The Klotho gene has been identified as an aging suppressor gene, and abnormality of its expression is correlated with a variety of diseases including kidney, heart, endocrine and metabolic system, and various cancers. Recently, accumulating body of evidence demonstrates that suppression of Klotho expression is closely associated with the pathogenesis of DN, which accompanied by activation of AKT/FoxO signaling pathway. Nevertheless, the exact role for Klotho and AKT/FoxO signaling pathway in DN is undetermined. This study was designed to investigate the expression of Klotho and AKT/FoxO signaling pathway, and to study the impact of oxidative stress, apoptosis, and autophagy on Klotho expression in vivo and in vitro in DN. Our finding may provide a new avenue to further understand the molecular mechanism of DN.

糖尿病(DM)是全球性导致终末期肾病(ESRD)的主要原因之一。尽管严格控制血糖、血压、代谢异常等，由DM引起的ESRD病人数剧增。糖尿病肾病(DN)是临床常见的重要慢性肾脏病，临床表现为尿蛋白排泄率增加及肾功能进行性恶化。蛋白尿不仅是反映早期肾损害的生化指标，而且是导致肾功能损害的独立因子。DN的发病机制极其复杂，大量研究表明肾素血管紧张素、炎性介质、转化生长因子、氧化应激等是重要参与者。Klotho基因被认定是衰老抑制基因，其表达异常与肾脏病、心血管疾病、内分泌、代谢疾病、癌症诸多疾病相关。最近研究发现DN患者Klotho基因表达减少,其作用是通过激活AKT/FoxO信号传导通路而完成。然而，有关Klotho及其AKT/FoxO信号传导通路在DN中的作用机制研究甚少。本实验拟通过体内、体外实验观察糖尿病肾病中肾脏组织Klotho及AKT/FoxO信号传导通路的表达，阐明氧化应激、细胞凋

糖尿病(DM)是全球性导致终末期肾病(ESRD)的主要原因之一。尽管严格控制血糖、血压、代谢异常等，由DM引起的ESRD病人数剧增。糖尿病肾病(DN)是临床常见的重要慢性肾脏病，临床表现为尿蛋白排泄率增加及肾功能进行性恶化。蛋白尿不仅是反映早期肾损害的生化指标，而且是导致肾功能损害的独立因子。DN的发病机制极其复杂，大量研究表明肾素血管紧张素、炎性介质、转化生长因子、氧化应激等是重要参与者。Klotho基因被认定是衰老抑制基因，其表达异常与肾脏病、心血管疾病、内分泌、代谢疾病、癌症诸多疾病相关。最近研究发现DN患者Klotho基因表达减少，其作用是通过激活AKT/FoxO信号传导通路而完成。然而，有关Klotho及其AKT/FoxO信号传导通路在DN中的作用机制研究甚少。经研究，我们发现他克莫司治疗以剂量依赖性方式降低Klotho表达；降低Klotho的表达加重他克莫司诱导的肾病程度及其氧化应激反应，针对Tac治疗的应答涉及Klotho缺陷小鼠中的PI3K-Akt-FoxO途径，这一发现为进一步了解DN的分子机制提供了新的途径。