Targeted disruption of the meprin metalloproteinase β gene protects against renal ischemia-reperfusion injury in mice

John Bylander, Qing Li, Ganesan Ramesh, Binzhi Zhang, W. Brian Reeves, Judith S. Bond

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Meprins are membrane-bound and secreted metalloproteinases consisting of α- and/or β-subunits that are highly expressed in mouse kidney proximal tubules. Previous studies have implied that the meprin α/β-isoform is deleterious when renal tissue is subjected to ischemia-reperfusion (I/R). To delineate the roles of the meprin isoforms in renal disease, we subjected mice deficient in meprin-β (KO) and their wild-type (WT) counterparts to I/R. WT mice were markedly more susceptible to renal injury after I/R than the meprin-β KO mice as determined by blood urea nitrogen levels. Urinary levels of inflammatory cytokines IL-6 and KC (CXCL1) were significantly higher in WT compared with meprin-β KO mice by 6 h post-I/R. At 96 h postischemia, kidney mRNA expression levels for tumor necrosis factor-α, transforming growth factor-β, inducible nitric oxide synthase, and heat shock protein-27 were significantly higher in the WT than meprin-β KO mice. For WT mice subjected to I/R, there was a rapid (3 h) redistribution of meprin β-subunits in cells in S3 segments of proximal tubules, followed by shedding of apical cell membrane and detachment of cells. These studies indicate that meprin-β is important in the pathogenesis of renal injury following I/R and that the redistribution of active meprin-α/β is a major contributor to renal injury and subsequent inflammation.

Original languageEnglish (US)
Pages (from-to)F480-F490
JournalAmerican Journal of Physiology - Renal Physiology
Volume294
Issue number3
DOIs
StatePublished - Mar 2008

Keywords

  • Inflammation
  • Kidney
  • Knockout mice
  • Metalloproteases

ASJC Scopus subject areas

  • Physiology
  • Urology

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