Matrix metalloproteinase-10 protects against acute kidney injury by augmenting epidermal growth factor receptor signaling.

Abstract

Matrix metalloproteinase-10 (MMP-10) is a zinc-dependent endopeptidase involved in regulating a wide range of biologic processes, such as apoptosis, cell proliferation, and tissue remodeling. However, the role of MMP-10 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we show that MMP-10 was upregulated in the kidneys and predominantly localized in the tubular epithelium in various models of AKI induced by ischemia/reperfusion (IR) or cisplatin. Overexpression of exogenous MMP-10 ameliorated AKI, manifested by decreased serum creatinine, blood urea nitrogen, tubular injury and apoptosis, and increased tubular regeneration. Conversely, knockdown of endogenous MMP-10 expression aggravated kidney injury. Interestingly, alleviation of AKI by MMP-10 in vivo was associated with the activation of epidermal growth factor receptor (EGFR) and its downstream AKT and extracellular signal-regulated kinase-1 and 2 (ERK1/2) signaling. Blockade of EGFR signaling by erlotinib abolished the MMP-10-mediated renal protection after AKI. In vitro, MMP-10 potentiated EGFR activation and protected kidney tubular cells against apoptosis induced by hypoxia/reoxygenation or cisplatin. MMP-10 was colocalized with heparin-binding EGF-like growth factor (HB-EGF) in vivo and activated it by a process of proteolytical cleavage in vitro. These studies identify HB-EGF as a previously unrecognized substrate of MMP-10. Our findings also underscore that MMP-10 can protect against AKI by augmenting EGFR signaling, leading to promotion of tubular cell survival and proliferation after injury.

• Authors: Chengxiao Hu, Yangyang Zuo, Qian Ren, Xiaoli Sun, Shan Zhou, Jinlin Liao, Xue Hong, Jinhua Miao, Lili Zhou, Youhua Liu
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 1 Pg. 70 (01 12 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 33436543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ErbB Receptors
• MMP10 protein, human
• Matrix Metalloproteinase 10

Topics

• Acute Kidney Injury (metabolism)
• ErbB Receptors (metabolism)
• Humans
• Matrix Metalloproteinase 10 (metabolism)
• Signal Transduction