HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/F480    most recent 00214.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bylander, J. Articles by Bond, J. S. Search for Related Content PubMed PubMed Citation Articles by Bylander, J. Articles by Bond, J. S.

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

Departments of ¹Biochemistry and Molecular Biology and ²Medicine, Penn State University College of Medicine, Hershey, Pennsylvania

Submitted 9 May 2007 ; accepted in final form 1 January 2008

Meprins are membrane-bound and secreted metalloproteinases consisting of - and/or β-subunits that are highly expressed in mouse kidney proximal tubules. Previous studies have implied that the meprin /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-, 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-/β is a major contributor to renal injury and subsequent inflammation.

metalloproteases; kidney; knockout mice; inflammation