title: Basement membrane protein nidogen-1 is a target of meprin β in cisplatin nephrotoxicity.
abstract: Meprins are oligomeric metalloproteinases that are abundantly expressed in the brush-border membranes of renal proximal tubules. During acute kidney injury (AKI) induced by cisplatin or ischemia-reperfusion, membrane-bound meprins are shed and their localization is altered from the apical membranes toward the basolateral surface of the proximal tubules. Meprins are capable of cleaving basement membrane proteins in vitro, however, it is not known whether meprins are able to degrade extracellular matrix proteins under pathophysiological conditions in vivo. The present study demonstrates that a basement membrane protein, nidogen-1, is cleaved and excreted in the urine of mice subjected to cisplatin-induced nephrotoxicity, a model of AKI. Cleaved nidogen-1 was not detected in the urine of untreated mice, but during the progression of cisplatin nephrotoxicity, the excretion of cleaved nidogen-1 increased in a time-dependent manner. The meprin inhibitor actinonin markedly prevented urinary excretion of the cleaved nidogen-1. In addition, meprin β-deficient mice, but not meprin α-deficient mice, subjected to cisplatin nephrotoxicity significantly suppressed excretion of cleaved nidogen-1, further suggesting that meprin β is involved in the cleavage of nidogen-1. These studies provide strong evidence for a pathophysiological link between meprin β and urinary excretion of cleaved nidogen-1 during cisplatin-induced AKI.
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA; University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, AR 72205, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Herzog
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA; University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, AR 72205, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Marisiddaiah
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA; University of Arkansas for Medical Sciences, Department of Pharmaceutical Sciences, Little Rock, AR 72205, USA.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Haun
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA; University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, AR 72205, USA; University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, AR 72205, USA. Electronic address: Kaushalgurp@uams.edu.
authors.forename: Gur P
authors.initials: GP
authors.lastname: Kaushal
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001485:Basement Membrane / Q000378:metabolism*; D002945:Cisplatin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006877:Hydroxamic Acids; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; C029967:nidogen; D008666:Metalloendopeptidases; C053833:meprin A; C010531:actinonin; D002945:Cisplatin
keywords: Actinonin; Acute kidney injury; Cisplatin; Meprin A; Meprin β; Meprin β-KO mice; Metalloproteinase; Nidogen