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

Abstract

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.

• Authors: John Bylander, Qing Li, Ganesan Ramesh, Binzhi Zhang, W Brian Reeves, Judith S Bond
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 294 Issue 3 Pg. F480-90 (Mar 2008) ISSN: 1931-857X [Print] United States
• PMID: 18172000 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers
• Isoenzymes
• RNA, Messenger
• Metalloendopeptidases
• meprin A

Topics

• Animals
• Biomarkers (metabolism)
• Isoenzymes (metabolism)
• Kidney (enzymology, metabolism, pathology)
• Kidney Diseases (enzymology, immunology, pathology)
• Kidney Function Tests
• Kidney Tubules, Proximal (enzymology)
• Metalloendopeptidases (genetics, metabolism, urine)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA, Messenger (metabolism)
• Reperfusion Injury (enzymology, immunology, pathology)