Role of meprin A in renal tubular epithelial cell injury.
Meprins are zinc-dependent metalloproteinases that are highly expressed in the brush-border membranes of both the kidney and the intestines. Meprins are capable of proteolytically degrading extracellular matrix proteins, proteolytically processing bioactive proteins, and play a role in inflammatory processes. In this study, the function of meprin A in the acute kidney injury (AKI) model of cisplatin nephrotoxicity was examined. Normal linear localization of meprin A in the brush border membranes of proximal tubules was altered in AKI. The meprin A alpha-subunit was detected in the urine of both control and cisplatin-treated mice. A cleaved product of the meprin A beta-subunit, undetected in the urine of control mice, was found to be significantly increased in the urine during the progression of cisplatin nephrotoxicity. The excretion of this beta-fragment was found to be before the rise in serum creatinine and blood urea nitrogen (BUN) suggesting usefulness as a biomarker for AKI. Pretreatment of mice with a meprin A inhibitor afforded protection from cisplatin nephrotoxicity as reflected by significant decreases in serum creatinine, BUN, and the excretion of kidney injury molecule-1. These decreases in serum and urine biomarkers were accompanied by significant decreases in histologic markers such as leukocyte infiltration and apoptosis. Meprin A appears to be an important therapeutic target and urinary excretion appears to be a potential biomarker of AKI.
Herzog
C
C
Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Seth
R
R
Shah
S V
SV
Kaushal
G P
GP
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin; D000072596:Hepatitis A Virus Cellular Receptor 1; D006877:Hydroxamic Acids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D007684:Kidney Tubules / Q000201:enzymology* / Q000473:pathology*; D007962:Leukocytes / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism* / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008871:Microvilli / Q000378:metabolism; D020033:Protein Isoforms / Q000652:urine; D011991:Receptors, Virus / Q000378:metabolism; D014018:Tissue Distribution
C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011991:Receptors, Virus; D008666:Metalloendopeptidases; C053833:meprin A; C010531:actinonin; D002945:Cisplatin