Targeted disruption of the meprin beta gene results in decreased renal ischemia/reperfusion injury in mice

Meprins are metalloproteinases consisting of alpha and/or beta subunits and are highly expressed in kidneys of mice. Inbred mouse strains that express very low levels of meprin alpha have been shown to be less susceptible to renal ischemia reperfusion (I/R) injury than mice expressing normal levels of meprin alpha. Bilateral renal I/R in normal meprin expressing mice resulted in a rapid [3 h] redistribution of meprin alpha and beta in cells in S3 segments of proximal tubules, followed by shedding of apical cell membrane and detachment of cells. Meprin redistribution and juxtamedullary tubular damage co‐localized with activated leukocytes. To explore the role of meprins in disease, mice with targeted disruption of the meprin beta gene were generated. These mice expressed the same levels of meprin alpha mRNA as wild‐type mice, however, the meprin alpha protein was not localized on the cell membrane and was secreted in an inactive form. By six hours of reperfusion, meprin beta deficient mice had better preservation of renal function than wild‐type mice as determined by lower plasma blood urea nitrogen (BUN) and lower Levels of IL‐6 and osteopontin mRNA. BUN levels were significantly lower in KO mice at all subsequent time points. At 96 hr post ischemia, mRNA expression levels for iNOS, TNF alpha, and HSP‐27 (indicators of inflammation) were significantly lower in the meprin beta deficient mice. These results indicate that meprins are important in the pathogenesis of renal injury following ischemia/reperfusion. We propose that the redistribution of active meprin alpha is a major contributor during I/R to renal injury and subsequent inflammation. (Supported by NIH DK 19691)