Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Kidney and Dialysis Institute of Shanghai, Shanghai, China; Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Kidney and Dialysis Institute of Shanghai, Shanghai, China; Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
Biochem Biophys Res Commun. 2021 Jun 25;559:48-55. doi: 10.1016/j.bbrc.2021.04.025. Epub 2021 Apr 28.
Podocyte injury is associated with albuminuria and the progression of diabetic nephropathy (DN). MiR-34a, a p53-regulated miRNA, directly targets SIRT1 and contributed to DN progression. MiR-34a represses SIRT1 to activate p53 and establish a positive feedback loop. However, whether p53/miR-34a/SIRT1 signaling is activated in podocytes and contributes to DN pathogenesis remains elusive. In this study, we observed that serum miR-34a level was positively correlated with podocyte injury in DN patients. The expression of acetylated p53 and miR-34a was upregulated, SIRT1was downregulated in glomeruli from patients with DN and STZ induced diabetic mice, as well as in human podocytes treated with advanced glycation end (AGE). MiR-34a antagonism in vitro and vivo in STZ induced diabetic mice developed alleviated glomerulus injury as reflected by attenuated albuminuria, reduced podocyte loss and restored autophagic flux. In human podocyte, inhibition of AGE formation by pyridoxamine prevented miR-34a dependent repression of SIRT1, p53 acetylation and activate podocyte autophagy in a dose-dependent manner. MiR-34a overexpression increases acetylation of p53 by translational repression of SIRT1. SIRT1 overexpression also impacts AGE induced apoptosis through deacetylating p53, whereas silencing of SIRT1 by EX527 attenuated the cytoprotective functions of miR-34a knockdown. Moreover, blockade of p53 acetylation significantly rescued miR-34a-induced apoptosis through SIRT1 restoration. Collectively, we demonstrate that by activation of p53, AGE induced the transcription of miR-34a, miR-34a in turn repressed SIRT1 to activate p53, resulting in a positive-feedback loop and contributing to podocyte injury. Targeting modulation of p53/miR-34a/SIRT1 feedback by miR-34a knockdown or overexpression of SIRT1 could rescue podocyte injury during DN.
足细胞损伤与白蛋白尿和糖尿病肾病 (DN) 的进展有关。miR-34a 是一种 p53 调节的 miRNA，可直接靶向 SIRT1 并促进 DN 的进展。miR-34a 通过抑制 SIRT1 来激活 p53 并建立正反馈环。然而，足细胞中是否激活了 p53/miR-34a/SIRT1 信号通路及其是否导致 DN 发病机制尚不清楚。在这项研究中，我们观察到 DN 患者血清 miR-34a 水平与足细胞损伤呈正相关。DN 患者和 STZ 诱导的糖尿病小鼠肾小球中以及人足细胞经晚期糖基化终产物 (AGE) 处理后，乙酰化 p53 和 miR-34a 的表达上调，SIRT1 的表达下调。在 STZ 诱导的糖尿病小鼠体内和体外，miR-34a 拮抗剂减轻了肾小球损伤，表现为白蛋白尿减少、足细胞丢失减少和自噬流恢复。在人足细胞中，吡哆胺抑制 AGE 形成以剂量依赖性方式防止 miR-34a 依赖性 SIRT1 抑制、p53 乙酰化和激活足细胞自噬。miR-34a 通过抑制 SIRT1 的翻译来增加 p53 的乙酰化。SIRT1 过表达也通过去乙酰化 p53 影响 AGE 诱导的细胞凋亡，而 EX527 沉默 SIRT1 则减弱了 miR-34a 敲低的细胞保护作用。此外，阻断 p53 乙酰化通过 SIRT1 恢复显著挽救了 miR-34a 诱导的细胞凋亡。综上所述，我们证明 AGE 通过激活 p53 诱导 miR-34a 的转录，miR-34a 反过来抑制 SIRT1 以激活 p53，从而形成正反馈环，导致足细胞损伤。通过 miR-34a 敲低或 SIRT1 的过表达靶向调节 p53/miR-34a/SIRT1 反馈可在 DN 期间挽救足细胞损伤。
