Distinct role of matrix metalloproteinase-3 in kidney injury molecule-1 shedding by kidney proximal tubular epithelial cells

Ai Ing Lim, Loretta Y.Y. Chan, Kar Neng Lai, Sydney C.W. Tang, Chui Wa Chow, Man Fai Lam, Joseph C.K. Leung

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Tubulointerstitial injury is a common pathway in progressive renal impairment and human proximal tubular epithelial cells (PTEC) play a crucial role in this process. Kidney injury molecule-1 (KIM-1) has received increasing attention due to its potential utility as the therapeutic target and biomarker for kidney injury. This study aims to explore the underlying mechanism regulating the release of KIM-1. Cultured primary human PTEC expressed and released KIM-1 from the apical surface through an ectodomain shedding process mediated by matrix metalloproteinase (MMP), independent of gene expression and protein synthesis. The constitutive KIM-1 shedding by PTEC was enhanced in a dose- and time-dependent manner by human serum albumin (HSA) or tumor necrosis factor-α (TNF-α), two important physiological stimuli found during kidney injury. Data from PCR array screening of MMPs gene expression in PTEC following activation by HSA or TNF-α, and from blocking experiments using either synthetic MMP inhibitors or MMP gene knockdown by siRNA, revealed that the constitutive and accelerated shedding of KIM-1 in cultured PTEC was mediated by MMP-3. Furthermore, the up-regulation of MMP-3 and KIM-1 release by PTEC was associated with generation of reactive oxygen species. In a mouse model of acute kidney injury induced by ischemia and reperfusion, increased expression of MMP-3 and KIM-1 as well as their co-localization were observed in kidney from ischemic but not in sham-operated mice. Taken together, these in vitro and in vivo evidences suggest that MMP-3 plays an inductive role in KIM-1 shedding by PTEC.

Original languageEnglish (US)
Pages (from-to)1040-1050
Number of pages11
JournalInternational Journal of Biochemistry and Cell Biology
Volume44
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology

Keywords

  • Ectodomain shedding
  • Kidney injury molecule
  • Matrix metalloproteinase
  • Proximal tubular epithelial cells
  • Reactive oxygen species

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