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Published on: June 8, 2022
Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge
Renee E Yura1, S Gaylen Bradley, Ganesan Ramesh
1Dept. of Biochemistry and Molecular Biology, The Pennsylvania State Univ. College of Medicine, 500 Univ. Drive, H171, Hershey, PA 17033, USA.
Abstract:
Meprin metalloproteases, composed of alpha and/or beta 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 alpha knockout (alphaKO), meprin beta knockout (betaKO), 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 alphaKO 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 betaKO mice. Serum cytokine profiles showed lower levels of IL-1beta and TNF-alpha in the meprin alphaKO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin alphaKO 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.
Insights
Meprin A, a metalloprotease, exacerbates kidney damage during endotoxemia. Meprin alpha knockout mice showed reduced inflammation and injury, suggesting meprin A drives endotoxic renal and urogenital disease.
Area of Science:
- Biochemistry
- Immunology
- Nephrology
Background:
- Meprin metalloproteases (alpha and/or beta subunits) are expressed in kidney proximal tubules and the urinary tract.
- Meprin metalloproteases are implicated in kidney diseases like ischemic acute renal failure and urinary tract infections.
Purpose of the Study:
- To investigate the role of meprin metalloproteases in endotoxemic acute renal failure.
- To compare the responses of meprin alpha knockout (alphaKO), meprin beta knockout (betaKO), and wild-type (WT) mice to endotoxin challenge.
Main Methods:
- Administered Escherichia coli lipopolysaccharide (LPS) to alphaKO, betaKO, and WT mice.
- Assessed systemic response by measuring blood urea nitrogen and nitric oxide levels.
- Analyzed serum cytokine profiles (IL-1beta, TNF-alpha) and evaluated bladder responses (edema, leukocyte infiltration, permeability) after LPS challenge.
Main Results:
- Meprin alphaKO mice exhibited significantly lower blood urea nitrogen and nitric oxide levels compared to WT and betaKO mice.
- Serum analysis revealed reduced IL-1beta and TNF-alpha levels in meprin alphaKO mice post-LPS challenge.
- Meprin alphaKO mice showed diminished bladder edema, leukocyte infiltration, and permeability when exposed to LPS.
Conclusions:
- Meprin A plays a significant role in the pathogenesis of endotoxemic acute renal failure.
- Meprin A contributes to the renal and urogenital inflammatory response to endotoxicity.
- Targeting meprin A may offer a therapeutic strategy for endotoxemic kidney injury.
