期刊
KIDNEY INTERNATIONAL
卷 95, 期 5, 页码 1167-1180出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2018.11.043
关键词
acute kidney injury; apoptosis; beta-catenin; FasL; MMP-7; proliferation
资金
- National Institutes of Health [DK064005, DK106049]
- National Science Foundation of China [81770737]
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 beta-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 beta-catenin, thereby priming kidney tubules for survival and regeneration.
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