Meprins are membrane-bound and secreted metalloproteinases consisting of and/or subunits that are highly expressed in mouse kidney proximal tubules. Previous studies have implied that the meprin / isoform is deleterious when renal tissue is subjected to ischemia/reperfusion (I/R). In order to delineate the roles of the meprin isoforms in renal disease, mice deficient in meprin (KO) and their wild-type (WT) counterparts were subjected to I/R. WT mice were markedly more susceptible to renal injury after I/R than the KO mice as determined by blood urea nitrogen levels. Urinary levels of inflammatory cytokines IL-6 and KC were significantly higher in WT compared to KO mice by 6 h post I/R. At 96 h post ischemia, kidney mRNA expression levels for TNF-, TGF-, iNOS, and HSP-27 were significantly higher in the WT compared to KO mice. For WT mice subjected to I/R there was a rapid [3 h] redistribution of meprin 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 is important in the pathogenesis of renal injury following I/R, and that the redistribution of active meprin / is a major contributor to renal injury and subsequent inflammation