Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT 06030-1405, USA.
Division of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Cells. 2022 Sep 5;11(17):2762. doi: 10.3390/cells11172762.
The TGF-β/Smad3 signaling pathway is an important process in the pathogenesis of kidney fibrosis. However, the molecular mechanisms are not completely elucidated. The current study examined the functional role of S100A4 in regulating TGF-β/Smad3 signaling in fibroblast activation and kidney fibrosis development. S100A4 was upregulated in the kidney in a murine model of renal fibrosis induced by folic acid nephropathy. Further, S100A4 was predominant in the tubulointerstitial cells of the kidney. Pharmacological inhibition of S100A4 with niclosamide significantly attenuated fibroblast activation, decreased collagen content, and reduced extracellular matrix protein expression in folic acid nephropathy. Overexpression of S100A4 in cultured renal fibroblasts significantly facilitated TGF-β1-induced activation of fibroblasts by increasing the expression of α-SMA, collagen-1 and fibronectin. In contrast, S100A4 knockdown prevented TGF-β1-induced activation of fibroblast and transcriptional activity of Smad3. Mechanistically, S100A4 interacts with Smad3 to stabilize the Smad3/Smad4 complex and promotes their translocation to the nucleus. In conclusion, S100A4 facilitates TGF-β signaling via interaction with Smad3 and promotes kidney fibrosis development. Manipulating S100A4 may provide a beneficial therapeutic strategy for chronic kidney disease.
TGF-β/Smad3 信号通路是肾脏纤维化发病机制中的一个重要过程。然而，其分子机制尚未完全阐明。本研究探讨了 S100A4 在调节成纤维细胞激活和肾脏纤维化发展过程中 TGF-β/Smad3 信号的功能作用。在叶酸肾病诱导的小鼠肾脏纤维化模型中，S100A4 在肾脏中上调。此外，S100A4 在肾脏的肾小管间质细胞中占优势。用尼氯硝唑抑制 S100A4 的药理作用可显著减弱成纤维细胞的激活，减少胶原含量，并减少叶酸肾病中的细胞外基质蛋白表达。在培养的肾成纤维细胞中过表达 S100A4 可通过增加α-SMA、胶原 1 和纤连蛋白的表达，显著促进 TGF-β1 诱导的成纤维细胞激活。相反，S100A4 的敲低可防止 TGF-β1 诱导的成纤维细胞激活和 Smad3 的转录活性。在机制上，S100A4 与 Smad3 相互作用，稳定 Smad3/Smad4 复合物，并促进它们向核内易位。总之，S100A4 通过与 Smad3 的相互作用促进 TGF-β 信号，从而促进肾脏纤维化的发展。操纵 S100A4 可能为慢性肾脏病提供有益的治疗策略。
