Abstract

Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes mellitus, and glomerular sclerosis and renal tubular interstitial fibrosis are the main pathological features. Current evidence indicates that the Notch pathway can mediate the impairment of renal tubular function and induce angiogenesis and renal interstitial fibrosis. This study was conducted to explore the potential signaling pathway through which Notch regulates oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose. mRNA and protein expression levels were assessed using real-time PCR and Western blot, respectively. The protein expression levels of Jaggedl, Notchl, pro-caspase-3, Drpl, and PGC-1α were increased by high glucose, but N-[N-(3,5-difluorohenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT; an inhibitor of the Notch signaling pathway) reversed these effects. Furthermore, DAPT reduced the mRNA expression of Jaggedl, Notchl, MnSOD2, Drpl, and PGC-1α in renal tubular epithelial cells induced by high glucose. In conclusion, the Notch signaling pathway may regulate oxidative damage and apoptosis in renal tubular epithelial cells induced by high glucose by regulating mitochondrial dynein and biogenesis genes, which can accelerate renal interstitial fibrosis in DN. The Notch signaling pathway might be a potential therapeutic target for DN, and DAPT might become a potential drug for the treatment of DN.

摘要

糖尿病肾病（DN）是糖尿病最常见、最严重的并发症之一，以肾小球硬化和肾小管间质纤维化为主要病理特征。目前的证据表明，Notch 通路可以介导肾小管功能的损害并诱导血管生成和肾间质纤维化。本研究旨在探索 Notch 调节高糖诱导的肾小管上皮细胞氧化损伤和凋亡的潜在信号通路。分别使用实时 PCR 和蛋白质印迹评估 mRNA 和蛋白质表达水平。Jaggedl、Notchl、pro-caspase-3、Drpl和PGC-1α的蛋白表达水平因高糖而升高，但N-[N-(3,5-difluorohenacetyl) -l-丙氨酰]-S-苯基甘氨酸叔丁酯（DAPT；Notch 信号通路的抑制剂）逆转了这些影响。此外，DAPT 降低了高糖诱导的肾小管上皮细胞中 Jagged1、Notch1、MnSOD2、Drpl 和 PGC-1α 的 mRNA 表达。综上所述，Notch信号通路可能通过调节线粒体动力蛋白和生物合成基因来调控高糖诱导的肾小管上皮细胞氧化损伤和凋亡，从而加速DN肾间质纤维化。Notch 信号通路可能是 DN 的潜在治疗靶点，而 DAPT 可能成为治疗 DN 的潜在药物。