Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
Research Center of Combined Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, People's Republic of China.
Am J Physiol Renal Physiol. 2021 Oct 1;321(4):F517-F526. doi: 10.1152/ajprenal.00085.2021. Epub 2021 Sep 6.
Increasing evidence shows that long noncoding RNAs (lncRNAs) play an important role in kidney disease. In this study, we investigated the role of the lncRNA growth arrest-specific 5 (GAS5) in the pathogenesis of renal fibrosis. We found that GAS5 was markedly decreased in the fibrotic kidney of a unilateral ureteral obstructive nephropathy mouse model. In addition, GAS5 was expressed in mouse tubular epithelial cells (mTECs) and interstitial fibroblasts in normal renal tissue and was especially highly expressed in the cytoplasm. In vitro experiments showed that GAS5 was downregulated by transforming growth factor-β1 (TGF-β1) in a dose- and time-dependent manner. Overexpression of GAS5 blocked TGF-β1-induced collagen type I and fibronectin expression and vice versa. Mechanistic experiments revealed that Smad3 but not Smad2 drove the regulation of GAS5. More importantly, GAS5 interacted with miR-142-5p and was involved in the renoprotective effect by participating in the competing endogenous RNA network. Finally, we also found that knockdown of GAS5 promoted TGF-β1-induced mouse tubular epithelial cell apoptosis via the Smad3 pathway. Taken together, our results uncovered a lncRNA/miRNA competing endogenous RNA network-based mechanism that modulates extracellular matrix formation and cell apoptosis via the Smad3 pathway. In this work, we mainly discuss long noncoding RNA growth arrest-specific 5 (GAS5), acting in a renoprotective role via the Smad3/miRNA-142-5p axis, that modulates extracellular matrix formation and cell apoptosis. Overexpression of GAS5 effectively blocked renal fibrosis in vitro. This study reveals that GAS5 may represent as a novel and precision therapeutic target for alleviating renal fibrosis.
越来越多的证据表明，长非编码 RNA（lncRNA）在肾脏疾病中发挥重要作用。在这项研究中，我们研究了 lncRNA 生长停滞特异性 5（GAS5）在肾纤维化发病机制中的作用。我们发现，单侧输尿管梗阻性肾病小鼠模型纤维化肾脏中 GAS5 明显减少。此外，GAS5 在正常肾组织中的小鼠肾小管上皮细胞（mTEC）和间质成纤维细胞中表达，并在细胞质中表达尤其高。体外实验表明，GAS5 被转化生长因子-β1（TGF-β1）以剂量和时间依赖的方式下调。GAS5 的过表达阻断了 TGF-β1 诱导的胶原 I 和纤维连接蛋白的表达，反之亦然。机制实验表明 Smad3 而不是 Smad2 驱动 GAS5 的调节。更重要的是，GAS5 与 miR-142-5p 相互作用，并通过参与竞争性内源性 RNA 网络参与肾保护作用。最后，我们还发现，GAS5 的敲低通过 Smad3 途径促进 TGF-β1 诱导的小鼠肾小管上皮细胞凋亡。总之，我们的研究结果揭示了一种基于 lncRNA/miRNA 竞争性内源性 RNA 网络的机制，该机制通过 Smad3 通路调节细胞外基质形成和细胞凋亡。在这项工作中，我们主要讨论长非编码 RNA 生长停滞特异性 5（GAS5），通过 Smad3/miRNA-142-5p 轴发挥肾保护作用，调节细胞外基质形成和细胞凋亡。GAS5 的过表达有效地阻止了体外肾纤维化。这项研究表明，GAS5 可能代表一种新的、精准的治疗靶点，可用于缓解肾纤维化。
