转录因子SOX4在肾纤维化过程中肾小管上皮细胞去分化和成纤维细胞激活中的关键作用。

Critical role of transcription factor SOX4 in tubular epithelial cell dedifferentiation and fibroblast activation during kidney fibrosis.

作者信息

Du Hao, Jiao Baihai, Xing Jian, Yang Dong, Tran Melanie, Wang Penghua, Hu Zhaoyong, Lefebvre Véronique, Zhou Dong, Wang Yanlin

机构信息

Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA; Department of Cell Biology, University of Connecticut School of Medicine, Farmington, Connecticut, USA.

Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, USA.

出版信息

Kidney Int. 2025 Sep 24. doi: 10.1016/j.kint.2025.08.030.

DOI:10.1016/j.kint.2025.08.030

PMID:41005570

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12548802/

Abstract

INTRODUCTION

Chronic kidney disease (CKD) is a widely prevalent health issue globally. A striking pathological feature of CKD is kidney fibrosis characterized by excessive production and deposition of extracellular matrix (ECM). Tubular epithelial cell (TEC) dedifferentiation and fibroblast activation contribute to the pathogenesis of kidney fibrosis. However, the molecular mechanisms underlying TEC dedifferentiation and fibroblast activation are not fully understood. Here, we investigated the role of SRY-box transcription factor 4 (SOX4) in regulating TEC dedifferentiation and fibroblast activation during the development of CKD.

METHODS

We generated global, TEC-specific, and fibroblast-specific SOX4 knockout mice. These mice were subjected to three preclinical models of kidney fibrosis induced by unilateral ureteral obstruction, ischemia-reperfusion injury, or high-dose folic acid to examine the role of SOX4 in TEC dedifferentiation and fibroblast activation during the development of kidney fibrosis. Cultured TECs and fibroblasts were employed to determine the role and molecular mechanisms of SOX4 in regulating TEC dedifferentiation and fibroblast activation in vitro.

RESULTS

SOX4 was induced in the injured kidneys but its deficiency inhibits TEC dedifferentiation, fibroblast activation and further impeded the development of kidney fibrosis in mice. In vitro, knockdown of SOX4 preserved the epithelial phenotype and inhibited fibroblast activation induced by transforming growth factor-β1 (TGF-β1). Mechanistically, SOX4 facilitated the TGF-β1-Smad3 signaling pathway to promote TEC dedifferentiation and fibroblast activation.

CONCLUSIONS

Our findings identify SOX4 as a critical factor in TEC dedifferentiation and fibroblast activation suggesting SOX4 may serve as a potential therapeutic target for the treatment of CKD.

摘要

引言

慢性肾脏病（CKD）是全球广泛流行的健康问题。CKD的一个显著病理特征是肾纤维化，其特点是细胞外基质（ECM）过度产生和沉积。肾小管上皮细胞（TEC）去分化和成纤维细胞活化促成了肾纤维化的发病机制。然而，TEC去分化和成纤维细胞活化背后的分子机制尚未完全阐明。在此，我们研究了SRY盒转录因子4（SOX4）在CKD发展过程中调节TEC去分化和成纤维细胞活化中的作用。

方法

我们构建了全身性、TEC特异性和成纤维细胞特异性SOX4基因敲除小鼠。这些小鼠接受了由单侧输尿管梗阻、缺血再灌注损伤或高剂量叶酸诱导的三种肾纤维化临床前模型，以研究SOX4在肾纤维化发展过程中对TEC去分化和成纤维细胞活化的作用。使用培养的TEC和成纤维细胞来确定SOX4在体外调节TEC去分化和成纤维细胞活化中的作用及分子机制。