Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Int J Mol Sci. 2024 May 11;25(10):5232. doi: 10.3390/ijms25105232.
Renal fibrosis (RF) stands as a pivotal pathological process in the advanced stages of chronic kidney disease (CKD), and impeding its progression is paramount for delaying the advancement of CKD. The miR-10 family, inclusive of miR-10a and miR-10b, has been implicated in the development of various fibrotic diseases. Nevertheless, the precise role of miR-10 in the development of RF remains enigmatic. In this study, we utilized both an in vivo model involving unilateral ureteral obstruction (UUO) in mice and an in vitro model employing TGF-β1 stimulation in HK-2 cells to unravel the mechanism underlying the involvement of miR-10a/b in RF. The findings revealed heightened expression of miR-10a and miR-10b in the kidneys of UUO mice, accompanied by a substantial increase in p-Smad3 and renal fibrosis-related proteins. Conversely, the deletion of these two genes led to a notable reduction in p-Smad3 levels and the alleviation of RF in mouse kidneys. In the in vitro model of TGF-β1-stimulated HK-2 cells, the co-overexpression of miR-10a and miR-10b fostered the phosphorylation of Smad3 and RF, while the inhibition of miR-10a and miR-10b resulted in a decrease in p-Smad3 levels and RF. Further research revealed that miR-10a and miR-10b, through binding to the 3'UTR region of Vasohibin-1 (VASH-1), suppressed the expression of VASH-1, thereby promoting the elevation of p-Smad3 and exacerbating the progression of RF. The miR-10 family may play a pivotal role in RF.
肾纤维化（RF）是慢性肾脏病（CKD）晚期的一个关键病理过程，阻止其进展对于延缓 CKD 的进展至关重要。miR-10 家族，包括 miR-10a 和 miR-10b，已被涉及到各种纤维化疾病的发展。然而，miR-10 在 RF 发展中的确切作用仍然是个谜。在这项研究中，我们使用了体内模型（单侧输尿管梗阻（UUO）在小鼠中）和体外模型（TGF-β1 刺激 HK-2 细胞）来揭示 miR-10a/b 参与 RF 的机制。研究结果表明，miR-10a 和 miR-10b 在 UUO 小鼠肾脏中的表达增加，伴随着 p-Smad3 和肾纤维化相关蛋白的大量增加。相反，这两个基因的缺失导致 p-Smad3 水平显著降低，并且减轻了小鼠肾脏中的 RF。在 TGF-β1 刺激的 HK-2 细胞的体外模型中，miR-10a 和 miR-10b 的共过表达促进了 Smad3 的磷酸化和 RF，而 miR-10a 和 miR-10b 的抑制导致 p-Smad3 水平降低和 RF 减少。进一步的研究表明，miR-10a 和 miR-10b 通过结合 Vasohibin-1（VASH-1）的 3'UTR 区域抑制了 VASH-1 的表达，从而促进了 p-Smad3 的升高并加剧了 RF 的进展。miR-10 家族可能在 RF 中发挥关键作用。
