PDF(Pubmed)
Abstract：
The glomerular podocyte, a terminally differentiated cell, is crucial for the integrity of the glomerular filtration barrier. The re-entry of podocytes into the mitotic phase results in injuries or death, known as mitotic catastrophe (MC), which significantly contributes to the progression of diabetic nephropathy (DN). Furthermore, P62-mediated autophagic flux has been shown to regulate DN-induced podocyte injury. Although previous studies, including ours, have demonstrated that ursolic acid (UA) mitigates podocyte injury by enhancing autophagy under high glucose conditions, the protective functions and potential regulatory mechanisms of UA against DN have not been fully elucidated. For aiming to investigate the regulatory mechanism of podocyte injuries in DN progression, and the protective function of UA treatment against DN progression, we utilized db/db mice and high glucose (HG)-induced podocyte models in vivo and in vitro, with or without UA administration. Our findings indicate that UA treatment reduced DN progression by improving biochemical indices. P62 accumulation led to Murine Double Minute gene 2 (MDM2)-regulated MC in podocytes during DN, which was ameliorated by UA through enhanced P62-mediated autophagy. Additionally, the overexpression of NF-κB p65 or TNF-α abolished the protective effects of UA both in vivo and in vitro. Overall, our results provide strong evidence that UA could be a potential therapeutic agent for DN, regulated by inhibiting podocyte MC through the NF-κB/MDM2/Notch1 pathway by targeting autophagic-P62 accumulation.
摘要：
肾小球足细胞,一个终末分化的细胞，对肾小球滤过屏障的完整性至关重要。足细胞重新进入有丝分裂期导致损伤或死亡，称为有丝分裂灾难（MC），显着促进糖尿病肾病（DN）的进展。此外，P62介导的自噬通量已显示出调节DN诱导的足细胞损伤。虽然以前的研究，包括我们的,已经证明熊果酸（UA）通过在高糖条件下增强自噬来减轻足细胞损伤，UA对DN的保护功能和潜在的调节机制尚未完全阐明.为探讨足细胞损伤在DN进展中的调控机制,和UA治疗对DN进展的保护功能，我们利用db/db小鼠和高糖（HG）诱导的足细胞模型在体内和体外，有或没有UA管理。我们的发现表明，UA治疗通过改善生化指标来减少DN进展。P62的积累导致小鼠双分钟基因2（MDM2）在DN期间在足细胞中调节MC，UA通过增强P62介导的自噬来改善。此外,NF-κBp65或TNF-α的过表达在体内和体外均消除了UA的保护作用。总的来说,我们的结果提供了强有力的证据，表明UA可能是DN的潜在治疗剂，通过靶向自噬P62积累通过NF-κB/MDM2/Notch1途径抑制足细胞MC进行调节。
