title: Differences in immunolocalization of Kim-1, RPA-1, and RPA-2 in kidneys of gentamicin-, cisplatin-, and valproic acid-treated rats: potential role of iNOS and nitrotyrosine.
abstract: The present study compared the immunolocalization of Kim-1, renal papillary antigen (RPA)-1, and RPA-2 with that of inducible nitric oxide synthase (iNOS) and nitrotyrosine in kidneys of gentamicin sulfate (Gen)- and cisplatin (Cis)-treated rats. The specificity of acute kidney injury (AKI) biomarkers, iNOS, and nitrotyrosine was evaluated by dosing rats with valproic acid (VPA). Sprague-Dawley (SD) rats were injected subcutaneously (sc) with 100 mg/kg/day of Gen for six or fourteen days; a single intraperitoneal (ip) dose of 1, 3, or 6 mg/kg of Cis; or 650 mg/kg/day of VPA (ip) for four days. In Gen-treated rats, Kim-1 was expressed in the epithelial cells, mainly in the S1/S2 segments but less so in the S3 segment, and RPA-1 was increased in the epithelial cells of collecting ducts (CD) in the cortex. Spatial expression of iNOS or nitrotyrosine with Kim-1 or RPA-1 was detected. In Cis-treated rats, Kim-1 was expressed only in the S3 segment cells, and RPA-1 and RPA-2 were increased in the epithelial cells of medullary CD or medullary loop of Henle (LH), respectively. Spatial expression of iNOS or nitrotyrosine with RPA-1 or RPA-2 was also identified. These findings suggest that peroxynitrite formation may be involved in the pathogenesis of Gen and Cis nephrotoxicity and that Kim-1, RPA-1, and RPA-2 have the potential to serve as site-specific biomarkers for Gen or Cis AKI.
authors.affiliation: Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA. jun.zhang@fda.hhs.gov
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Peter L
authors.initials: PL
authors.lastname: Goering
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Espandiari
authors.forename: Martin
authors.initials: M
authors.lastname: Shaw
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Vaidya
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Brown
authors.forename: Joe
authors.initials: J
authors.lastname: Keenan
authors.forename: Cormac G
authors.initials: CG
authors.lastname: Kilty
authors.forename: Nakissa
authors.initials: N
authors.lastname: Sadrieh
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology*; D005839:Gentamicins / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism*; D010784:Photomicrography; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000941:Antigens; D015815:Cell Adhesion Molecules; D002945:Cisplatin; D005839:Gentamicins; D052247:Nitric Oxide Synthase Type II; D014443:Tyrosine; D014635:Valproic Acid; C110936:Havcr1 protein, rat; C002744:3-nitrotyrosine; C496318:Nos2 protein, rat