Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
Cell Signal. 2023 Oct;110:110801. doi: 10.1016/j.cellsig.2023.110801. Epub 2023 Jul 9.
The pathogenesis of renal ischemic diseases remains unclear. In this study, we demonstrate the induction of microRNA-132-3p (miR-132-3p) in ischemic acute kidney injury (AKI) and cultured renal tubular cells under oxidative stress. miR-132-3p mimic increased apoptosis in renal tubular cells and enhanced ischemic AKI in mice, whereas miR-132-3p inhibition offered protective effects. We analyzed miR-132-3p target genes through bioinformatic analysis and Sirt1 was predicted as the target gene of miR-132-3p. Luciferase microRNA target reporter assay further verified Sirt1 as a direct target of miR-132-3p. In cultured tubular cells and mouse kidneys, IRI and HO treatment repressed Sirt1 and PGC-1α/NRF2/HO-1 expression, whereas anti-miR-132-3p preserved Sirt1 and PGC-1α/NRF2/HO-1 expression. In renal tubular, Sirt1 inhibitor suppressed PGC1-1α/NRF2/HO-1 expression and aggravated tubular apoptosis. Together, the results suggest that miR-132-3p induction aggravates ischemic AKI and oxidative stress by repressing Sirt1 expression, and miR-132-3p inhibition offers renal protection and may be a potential therapeutic target.
肾缺血性疾病的发病机制尚不清楚。在这项研究中，我们证明了 microRNA-132-3p（miR-132-3p）在缺血性急性肾损伤（AKI）和氧化应激下培养的肾小管细胞中的诱导作用。miR-132-3p 模拟物增加肾小管细胞凋亡，并增强小鼠缺血性 AKI，而 miR-132-3p 抑制则提供保护作用。我们通过生物信息学分析分析了 miR-132-3p 的靶基因，预测 Sirt1 是 miR-132-3p 的靶基因。荧光素酶 microRNA 靶标报告基因测定进一步证实 Sirt1 是 miR-132-3p 的直接靶基因。在培养的肾小管细胞和小鼠肾脏中，IRI 和 HO 处理抑制 Sirt1 和 PGC-1α/NRF2/HO-1 的表达，而抗 miR-132-3p 则保留 Sirt1 和 PGC-1α/NRF2/HO-1 的表达。在肾小管中，Sirt1 抑制剂抑制 PGC1-1α/NRF2/HO-1 的表达并加重肾小管细胞凋亡。综上所述，这些结果表明，miR-132-3p 通过抑制 Sirt1 表达诱导加重缺血性 AKI 和氧化应激，miR-132-3p 抑制可提供肾脏保护作用，可能是一种潜在的治疗靶点。
