Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China.
Mol Med Rep. 2020 Nov;22(5):4017-4030. doi: 10.3892/mmr.2020.11488. Epub 2020 Sep 2.
Sox9 is important for multiple aspects of development, such as testis, pancreas and heart development. Previous studies have reported that Sox9 induced epithelial‑mesenchymal transition (EMT) and extracellular matrix (ECM) production in organ fibrosis and associated diseases, such as vascular calcification. However, to the best of our knowledge, the role and underlying mechanism of action of Sox9 in renal fibrogenesis remains unknown. The results of the present study revealed that Sox9 expression levels were upregulated in the tubular epithelial cells of a rat model of obstructive nephropathy. Furthermore, the overexpression of Sox9 in NRK‑52E cells was discovered to promote renal tubular EMT and ECM aggregation, and these fibrogenic actions were potentiated by TGF‑β1. Notably, RNA‑sequencing analysis indicated the possible regulatory role of the PI3K/AKT signaling pathway in Sox9‑mediated renal tubular EMT and ECM aggregation. It was further demonstrated that the expression levels of phosphorylated AKT were upregulated in NRK‑52E cells overexpressing Sox9, while the PI3K inhibitors, LY29002 and wortmannin, inhibited the renal tubular EMT and ECM aggregation induced by the overexpression of Sox9 in NEK‑52E cells. In conclusion, the findings of the present study suggested that Sox9 may serve a profibrotic role in the development of renal tubular EMT and ECM aggregation via the PI3K/AKT signaling pathway. Therefore, Sox9 may be considered as a promising target for treating renal fibrosis.
Sox9 在多个发育方面都很重要，例如睾丸、胰腺和心脏发育。先前的研究报告称，Sox9 在器官纤维化和相关疾病（如血管钙化）中诱导上皮-间充质转化（EMT）和细胞外基质（ECM）产生。然而，据我们所知，Sox9 在肾纤维化中的作用和潜在作用机制尚不清楚。本研究结果表明，Sox9 的表达水平在梗阻性肾病大鼠模型的肾小管上皮细胞中上调。此外，发现 NRK-52E 细胞中 Sox9 的过表达可促进肾小管 EMT 和 ECM 聚集，并且这些纤维生成作用被 TGF-β1 增强。值得注意的是，RNA 测序分析表明 PI3K/AKT 信号通路在 Sox9 介导的肾小管 EMT 和 ECM 聚集中可能具有调节作用。进一步表明，过表达 Sox9 的 NRK-52E 细胞中磷酸化 AKT 的表达水平上调，而 PI3K 抑制剂 LY29002 和wortmannin 抑制了 NEK-52E 细胞中 Sox9 过表达诱导的肾小管 EMT 和 ECM 聚集。综上所述，本研究结果表明 Sox9 可能通过 PI3K/AKT 信号通路在肾小管 EMT 和 ECM 聚集的发展中发挥促纤维化作用。因此，Sox9 可能被认为是治疗肾纤维化的有前途的靶标。
