Meprin metalloproteases, composed of and/or 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 knockout (KO), 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 i.p. 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 to WT and meprin KO mice. Serum cytokine profiles showed lower levels of IL-1 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. The data indicate that meprin A contributes to the renal and urogenital pathogenesis of endotoxicity.