Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration.

Abstract

Matrix metalloproteinase-7 (MMP-7) is a secreted endopeptidase that degrades a broad range of substrates. Recent studies have identified MMP-7 as an early biomarker to predict severe acute kidney injury (AKI) and poor outcomes after cardiac surgery; however, the role of MMP-7 in the pathogenesis of AKI is unknown. In this study, we investigated the expression of MMP-7 and the impact of MMP-7 deficiency in several models of AKI. MMP-7 was induced in renal tubules following ischemia/ reperfusion injury or cisplatin administration, and in folic acid-induced AKI. MMP-7 knockout mice experienced higher mortality, elevated serum creatinine, and more severe histologic lesions after ischemic or toxic insults. Tubular apoptosis and interstitial inflammation were more prominent in MMP-7 knockout kidneys. These histologic changes were accompanied by increased expression of FasL and other components of the extrinsic apoptotic pathway, as well as increased expression of pro-inflammatory chemokines. In a rescue experiment, exogenous MMP-7 ameliorated kidney injury in MMP-7 knockout mice after ischemia/reperfusion. In vitro, MMP-7 protected tubular epithelial cells against apoptosis by directly degrading FasL. In isolated tubules ex vivo, MMP-7 promoted cell proliferation by degrading E-cadherin and thereby liberating β-catenin, priming renal tubules for regeneration. Taken together, these results suggest that induction of MMP-7 is protective in AKI by degrading FasL and mobilizing β-catenin, thereby priming kidney tubules for survival and regeneration.

• Authors: Haiyan Fu, Dong Zhou, Haili Zhu, Jinlin Liao, Lin Lin, Xue Hong, Fan Fan Hou, Youhua Liu
• Journal: Kidney international (Kidney Int) Vol. 95 Issue 5 Pg. 1167-1180 (05 2019) ISSN: 1523-1755 [Electronic] United States
• PMID: 30878215 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CTNNB1 protein, mouse
• Fas Ligand Protein
• Fasl protein, mouse
• beta Catenin
• Folic Acid
• Matrix Metalloproteinase 7

Topics

• Acute Kidney Injury (chemically induced, pathology)
• Animals
• Apoptosis (physiology)
• Cell Proliferation (physiology)
• Cell Survival (physiology)
• Disease Models, Animal
• Epithelial Cells (metabolism)
• Fas Ligand Protein (metabolism)
• Folic Acid (toxicity)
• Humans
• Kidney Tubules (blood supply, drug effects, pathology)
• Matrix Metalloproteinase 7 (genetics, metabolism)
• Mice
• Mice, Knockout
• Proteolysis
• Regeneration (physiology)
• Reperfusion Injury (pathology)
• Signal Transduction (physiology)
• beta Catenin (metabolism)