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This Article Full Text Full Text (PDF) All Versions of this Article: 296/1/F135    most recent 90524.2008v1 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 PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yura, R. E. Articles by Bond, J. S. Search for Related Content PubMed PubMed Citation Articles by Yura, R. E. Articles by Bond, J. S.

Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge

¹Department of Biochemistry and Molecular Biology and ²Division of Nephrology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Submitted 3 September 2008 ; accepted in final form 27 October 2008

Meprin metalloproteases, composed of and/or β subunits, consist of membrane-bound and secreted forms that are abundantly expressed in proximal tubules of the kidney as well as secreted into the urinary tract. Previous studies indicated that meprin metalloproteases play a role in pathological conditions such as ischemic acute renal failure and urinary tract infection. The aim of this work was to examine the role of meprins in endotoxemic acute renal failure using meprin knockout (KO), meprin β knockout (βKO), and wild-type (WT) mice. Differences among the responses of the genotypes were observed as early as 1 h after challenge with 2.5 mg/kg ip Escherichia coli LPS, establishing roles for meprins in the endotoxemic response. Meprin KO mice displayed lower blood urea nitrogen levels and decreased nitric oxide levels, indicative of a decreased systemic response to LPS compared with WT and meprin βKO mice. Serum cytokine profiles showed lower levels of IL-1β and TNF– in the meprin KO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin KO mice were also hyporesponsive to LPS administered to the bladder, exhibiting significantly less bladder edema, leukocyte infiltration, and bladder permeability than WT mice. These data indicate that meprin A contributes to the renal and urogenital pathogenesis of endotoxicity.

knockout mice; lipopolysaccharide; kidney; metalloproteinase