Matrix metalloproteinase-10 promotes kidney fibrosis by transactivating β-catenin signaling

  • Cell Death Discov. 2025 May 17;11(1):241. doi: 10.1038/s41420-025-02521-w.
Xiaoli Sun  1  2 ,  Qian Ren  1  2 ,  Xi Liu  1  2 ,  Huishi Tan  1  2 ,  Zhanji Zhan  1  2 ,  Enqing Lin  1  2 ,  Yinyi Long  1  2 ,  Xue Hong  1  2 ,  Lili Zhou  3  4 ,  Youhua Liu  5  6
Affiliations
  • 1. State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2. Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China.
  • 3. State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 4. Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China. [email protected].
  • 5. State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 6. Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, China. [email protected].
PMID: 40382334 DOI: 10.1038/s41420-025-02521-w
Abstract

Kidney fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) and serves as a hallmark of chronic kidney disease (CKD). The turnover of ECM is controlled by a family of Matrix Metalloproteinases (MMPs), endopeptidases that play a crucial role in ECM remodeling and Other cellular processes. In this study, we demonstrate that MMP-10 was upregulated in a variety of animal models of kidney fibrosis and human kidney biopsies from CKD patients. Bioinformatics analyses and experimental validation reveal that MMP-10 activated β-catenin in a Wnt-independent fashion. Knockdown of endogenous MMP-10 expression in vivo inhibited β-catenin activation and ameliorated kidney injury and fibrotic lesions, whereas over-expression of exogenous MMP-10 aggravated β-catenin activation and kidney fibrosis after injury. We found that MMP-10 cleaved and activated heparin-binding EGF-like growth factor (HB-EGF) via ectodomain shedding, leading to EGF receptor (EGFR) tyrosine phosphorylation and β-catenin transactivation via a cascade of events involving extracellular signal-regulated kinases and glycogen synthase kinase-3β. Consistently, treatment with erlotinib, a small-molecule EGFR Inhibitor, effectively mitigated MMP-10-mediated kidney injury and fibrotic lesions in a dose-dependent fashion. Furthermore, β-catenin activation reciprocally upregulated the expression of MMP-10, thereby perpetuating kidney damage by forming a vicious cycle. Collectively, these results underscore that MMP-10 promotes kidney fibrosis through EGFR-mediated transactivating β-catenin in a Wnt-independent fashion. Our findings suggest that targeting MMP-10 could be a novel strategy for treatment of fibrotic CKD.

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