Long non-coding RNAs (lncRNAs) are a group of epigenetic regulators that have been implicated in kidney diseases including acute kidney injury (AKI). However, very little is known about the specific lncRNAs involved in AKI and the mechanisms underlying their pathologic roles. Here, we report a new lncRNA derived from the pseudogene , which mediates ischemic AKI by interacting with and promoting the degradation of mir-668, a kidney-protective microRNA. GSTM3P1 and its mouse orthologue Gstm2-ps1 were induced by hypoxia in cultured kidney proximal tubular cells. In mouse kidneys, Gstm2-ps1 was significantly upregulated in proximal tubules at an early stage of ischemic AKI. This transient induction of Gstm2-ps1 depends on G3BP1, a key component in stress granules. GSTM3P1 overexpression increased kidney proximal tubular apoptosis after ATP depletion, which was rescued by mir-668. Notably, kidney proximal tubule-specific knockout of Gstm2-ps1 protected mice from ischemic AKI, as evidenced by improved kidney function, diminished tubular damage and apoptosis, and reduced kidney injury biomarker (NGAL) induction. To test the therapeutic potential, Gstm2-ps1 siRNAs were introduced into cultured mouse proximal tubular cells or administered to mice. In cultured cells, Gstm2-ps1 knockdown suppressed ATP depletion–associated apoptosis. In mice, Gstm2-ps1 knockdown ameliorated ischemic AKI. Mechanistically, both GSTM3P1 and Gstm2-ps1 possessed mir-668 binding sites and downregulated the mature form of mir-668. Specifically, GSTM3P1 directly bound to mature mir-668 to induce its decay via target-directed microRNA degradation. Thus, our results identify GSTM3P1 as a novel lncRNA that promotes kidney tubular cell death in AKI by binding mir-668 to inducing its degradation.

中文翻译：

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假基因 GSTM3P1 衍生的长非编码 RNA 通过肾脏保护性 mir-668 的靶向 microRNA 降解促进缺血性急性肾损伤


长非编码 RNA (lncRNA) 是一组表观遗传调节因子，与包括急性肾损伤 (AKI) 在内的肾脏疾病有关。然而，人们对 AKI 中涉及的特定 lncRNA 及其病理作用的机制知之甚少。在这里，我们报道了一种源自假基因的新 lncRNA，它通过与 mir-668（一种肾脏保护性 microRNA）相互作用并促进其降解来介导缺血性 AKI。 GSTM3P1 及其小鼠直系同源物 Gstm2-ps1 在培养的肾近端肾小管细胞中由缺氧诱导。在小鼠肾脏中，缺血性 AKI 的早期阶段，近曲小管中的 Gstm2-ps1 显着上调。 Gstm2-ps1 的这种瞬时诱导依赖于 G3BP1，它是应激颗粒的关键成分。 GSTM3P1 过表达会增加 ATP 耗尽后肾近端肾小管的凋亡，而 mir-668 可以挽救这种情况。值得注意的是，肾近曲小管特异性敲除 Gstm2-ps1 可保护小鼠免受缺血性 AKI，肾功能改善、肾小管损伤和细胞凋亡减少以及肾损伤生物标志物 (NGAL) 诱导减少就证明了这一点。为了测试治疗潜力，将 Gstm2-ps1 siRNA 引入培养的小鼠近端肾小管细胞中或给予小鼠。在培养细胞中，Gstm2-ps1 敲低可抑制 ATP 耗竭相关的细胞凋亡。在小鼠中，Gstm2-ps1 敲除可改善缺血性 AKI。从机制上讲，GSTM3P1 和 Gstm2-ps1 都具有 mir-668 结合位点，并下调 mir-668 的成熟形式。具体来说，GSTM3P1 直接与成熟的 mir-668 结合，通过靶向的 microRNA 降解诱导其衰变。因此，我们的结果将 GSTM3P1 确定为一种新型 lncRNA，通过结合 mir-668 诱导其降解，促进 AKI 中肾小管细胞死亡。