Yang Lei, Liang Baozhu, Li Jingxin, Zhang Xiaoyan, Chen Hong, Sun Jia, Zhang Zhen
Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Cell Signal. 2022 Feb;90:110206. doi: 10.1016/j.cellsig.2021.110206. Epub 2021 Nov 29.
Excessive accumulation of advanced glycation end products (AGEs) contributes to autophagy interruption on podocytes and insufficient autophagy on podocytes is accountable to podocyte injury and eventually accelerates the advancement of DN. SGLT2 inhibitors have been confirmed excellent renoprotection in DN whereas the mechanism for such benefit is not fully illustrated. Here, we report dapagliflozin, an SGLT2 inhibitor, ameliorated the pro-inflammatory cytokines release and apoptosis level concomitant with increasing Synaptopodin level on AGE-induced podocytes. Furthermore, dapagliflozin manifested autophagy promotion on AGE-induced podocytes as evident by the upregulated Beclin and LC3II/LC3I ratio levels attendant with the shrunk p62 level. However, The protective effect of dapagliflozin was blunted by 3-MA, an autophagy inhibitor. Additionally, the effect of dapagliflozin on autophagy was relevant to the regulation of the AMPK-mTOR signal pathway. Taken together, dapagliflozin effectively mitigated AGE-induced podocyte injury through AMPK-mTOR mediated upregulation of autophagy. It may offer a novel mechanism to further elucidate the renoprotective effect on SGLT2 inhibitors.
晚期糖基化终末产物（AGEs）的过度积累会导致足细胞自噬中断，而足细胞自噬不足会导致足细胞损伤，并最终加速糖尿病肾病（DN）的进展。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂已被证实在DN中具有出色的肾脏保护作用，但其这种益处的机制尚未完全阐明。在此，我们报告了SGLT2抑制剂达格列净可改善AGE诱导的足细胞中促炎细胞因子的释放和凋亡水平，同时增加突触足蛋白水平。此外，达格列净在AGE诱导的足细胞中表现出促进自噬的作用，表现为Beclin和LC3II/LC3I比值水平上调，伴随p62水平降低。然而，自噬抑制剂3-甲基腺嘌呤（3-MA）削弱了达格列净的保护作用。此外，达格列净对自噬的影响与AMPK-雷帕霉素靶蛋白（mTOR）信号通路的调节有关。综上所述，达格列净通过AMPK-mTOR介导的自噬上调有效减轻了AGE诱导的足细胞损伤。它可能为进一步阐明SGLT2抑制剂的肾脏保护作用提供一种新机制。
