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

Renee E. Yura, S. Gaylen Bradley, Ganesan Ramesh, W. Brian Reeves, Judith S. Bond

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Meprin metalloproteases, composed of α 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 α knockout (αKO), 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 αKO 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-α in the meprin αKO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin αKO 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.

Original languageEnglish (US)
Pages (from-to)F135-F144
JournalAmerican Journal of Physiology - Renal Physiology
Volume296
Issue number1
DOIs
StatePublished - Jan 2009

Keywords

  • Kidney
  • Knockout mice
  • Lipopolysaccharide
  • Metalloproteinase

ASJC Scopus subject areas

  • Physiology
  • Urology

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