Targeted disruption of the meprin metalloproteinase beta gene protects against renal ischemia-reperfusion injury in mice.
Meprins are membrane-bound and secreted metalloproteinases consisting of alpha- and/or beta-subunits that are highly expressed in mouse kidney proximal tubules. Previous studies have implied that the meprin alpha/beta-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-beta (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-beta 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-beta KO mice by 6 h post-I/R. At 96 h postischemia, kidney mRNA expression levels for tumor necrosis factor-alpha, transforming growth factor-beta, inducible nitric oxide synthase, and heat shock protein-27 were significantly higher in the WT than meprin-beta KO mice. For WT mice subjected to I/R, there was a rapid (3 h) redistribution of meprin beta-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-beta is important in the pathogenesis of renal injury following I/R and that the redistribution of active meprin-alpha/beta is a major contributor to renal injury and subsequent inflammation.
Bylander
John
J
Deparment of Biochemistry and Molecular Biology, Penn State University College of Medicine, 500 Univ. Drive, Hershey, PA 17033, USA.
Li
Qing
Q
Ramesh
Ganesan
G
Zhang
Binzhi
B
Reeves
W Brian
WB
Bond
Judith S
JS
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000276:immunology / Q000473:pathology
D015415:Biomarkers; D007527:Isoenzymes; D012333:RNA, Messenger; D008666:Metalloendopeptidases; C053833:meprin A