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

Toxicol Pathol. 2009 Aug;37(5):629-43. doi: 10.1177/0192623309339605. Epub 2009 Jun 17.

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.

MeSH terms

  • Animals
  • Antigens / metabolism*
  • Cell Adhesion Molecules / metabolism*
  • Cisplatin / pharmacology*
  • Gentamicins / pharmacology*
  • Immunohistochemistry
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / chemically induced
  • Kidney Diseases / metabolism
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Nitric Oxide Synthase Type II / biosynthesis
  • Nitric Oxide Synthase Type II / metabolism*
  • Photomicrography
  • Rats
  • Rats, Sprague-Dawley
  • Statistics, Nonparametric
  • Tyrosine / analogs & derivatives*
  • Tyrosine / biosynthesis
  • Tyrosine / metabolism
  • Valproic Acid / pharmacology*

Substances

  • Antigens
  • Cell Adhesion Molecules
  • Gentamicins
  • Havcr1protein, rat
  • 3-nitrotyrosine
  • Tyrosine
  • Valproic Acid
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Cisplatin