Kidney fibrosis is mediated by GARP-restricted TGF-β activation in fibroblasts
6 affiliations
- 1Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Multi-organ Injury Prevention and Treatment; National Clinical Research Center for Kidney and Urological Diseases, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, Guangdong, China.
- 2The First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- 3School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
- 4Molecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China.
- 5Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
- 6Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore.
Abstract
TGF-β is a central driver of kidney fibrosis, a common pathological hallmark of chronic kidney disease (CKD). Initiation of TGF-β signaling requires not only its synthesis but also the conversion of latent TGF-β to its bioactive form. However, the mechanisms governing TGF-β activation in the kidney and their contribution to kidney fibrosis remain poorly understood. Glycoprotein A repetitions predominant (GARP) anchors latent TGF-β on the cell surface and facilitates its bioactive release. Here, we show that GARP-mediated TGF-β activation promotes kidney fibrosis. GARP was upregulated in both human and mouse CKD kidneys, predominantly in fibroblasts, and was induced by TNF in an NF-κB–dependent fashion. In multiple mouse models of kidney fibrosis, either global or fibroblast-specific deletion of GARP markedly reduced fibrosis. Mechanistically, GARP enables sustained production of active TGF-β, thereby amplifying fibroblast stimulation. Deletion of GARP in kidney fibroblasts lowered active TGF-β levels and attenuated fibroblast activation, whereas GARP overexpression enhanced TGF-β signaling. Notably, tamoxifen-induced deletion of GARP after fibrosis onset attenuated kidney fibrosis. Together, our findings identify GARP-mediated release of active TGF-β as a critical step in sustaining fibroblast activation during kidney fibrosis and highlight GARP as a promising therapeutic target for CKD.
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BibTeX
@article{chen2026kidney,
title = {{Kidney fibrosis is mediated by GARP-restricted TGF-β activation in fibroblasts}},
author = {Yintong Chen and Weiwei Xu and Jieli Yu and Pei Deng and Nianping Liu and Yinyin Li and Hui Zhou and Hong Zhou and Jianchuan Wang and Bo Zhao and Florian Winau and Fan Fan Hou and Yu Hu},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.203039},
url = {https://doi.org/10.1172/jci.insight.203039},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Kidney fibrosis is mediated by GARP-restricted TGF-β activation in fibroblasts
AU - Yintong Chen
AU - Weiwei Xu
AU - Jieli Yu
AU - Pei Deng
AU - Nianping Liu
AU - Yinyin Li
AU - Hui Zhou
AU - Hong Zhou
AU - Jianchuan Wang
AU - Bo Zhao
AU - Florian Winau
AU - Fan Fan Hou
AU - Yu Hu
PY - 2026
DA - 2026/09/17
JO - JCI Insight
DO - 10.1172/jci.insight.203039
UR - https://doi.org/10.1172/jci.insight.203039
AB - TGF-β is a central driver of kidney fibrosis, a common pathological hallmark of chronic kidney disease (CKD). Initiation of TGF-β signaling requires not only its synthesis but also the conversion of latent TGF-β to its bioactive form. However, the mechanisms governing TGF-β activation in the kidney and their contribution to kidney fibrosis remain poorly understood. Glycoprotein A repetitions predominant (GARP) anchors latent TGF-β on the cell surface and facilitates its bioactive release. Here, we show that GARP-mediated TGF-β activation promotes kidney fibrosis. GARP was upregulated in both human and mouse CKD kidneys, predominantly in fibroblasts, and was induced by TNF in an NF-κB–dependent fashion. In multiple mouse models of kidney fibrosis, either global or fibroblast-specific deletion of GARP markedly reduced fibrosis. Mechanistically, GARP enables sustained production of active TGF-β, thereby amplifying fibroblast stimulation. Deletion of GARP in kidney fibroblasts lowered active TGF-β levels and attenuated fibroblast activation, whereas GARP overexpression enhanced TGF-β signaling. Notably, tamoxifen-induced deletion of GARP after fibrosis onset attenuated kidney fibrosis. Together, our findings identify GARP-mediated release of active TGF-β as a critical step in sustaining fibroblast activation during kidney fibrosis and highlight GARP as a promising therapeutic target for CKD.
SN - 2379-3708
ER -