Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis
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...
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MDPI AG
2022-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/17/2762 |
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| author | Jia Wen Baihai Jiao Melanie Tran Yanlin Wang |
| author_facet | Jia Wen Baihai Jiao Melanie Tran Yanlin Wang |
| author_sort | Jia Wen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T01:56:13Z |
| format | Article |
| id | doaj.art-ad639f9f112945d2ac42cf0249b3bb11 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:56:13Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ad639f9f112945d2ac42cf0249b3bb112023-11-23T12:56:33ZengMDPI AGCells2073-44092022-09-011117276210.3390/cells11172762Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal FibrosisJia Wen0Baihai Jiao1Melanie Tran2Yanlin Wang3Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT 06030-1405, USADivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT 06030-1405, USADivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT 06030-1405, USADivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT 06030-1405, USAThe 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.https://www.mdpi.com/2073-4409/11/17/2762Smad3S100A4fibroblastrenal fibrosis |
| spellingShingle | Jia Wen Baihai Jiao Melanie Tran Yanlin Wang Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis Cells Smad3 S100A4 fibroblast renal fibrosis |
| title | Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis |
| title_full | Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis |
| title_fullStr | Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis |
| title_full_unstemmed | Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis |
| title_short | Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis |
| title_sort | pharmacological inhibition of s100a4 attenuates fibroblast activation and renal fibrosis |
| topic | Smad3 S100A4 fibroblast renal fibrosis |
| url | https://www.mdpi.com/2073-4409/11/17/2762 |
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