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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

¹ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
² Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland, USA
³ Argutus Medical Ltd., Dublin, Ireland
⁴ Harvard Institutes of Medicine, Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Address correspondence to: Jun Zhang, M.D., M.S., Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration (HFD-910), 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, U.S.A.; e-mail:jun.zhang{at}fda.hhs.gov.

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.

Key Words: cisplatin • gentamicin • Kim-1 • nitrotyrosine • RPA-1 • RPA-2

Abbreviations: AKI, acute kidney injury • CD, collecting ducts • Cis, cisplatin • DCT, distal convoluted tubule • Gen, gentamicin sulfate • IHC, immunohistochemistry • iNOS, inducible nitric oxide synthase • Kim-1, kidney injury molecule-1 • LH, loop of Henle • NO, nitric oxide • RPA-1, renal papillary antigen-1 • RPA-2, renal papillary antigen-2 • S1/S2 segments, proximal convoluted tubules • S3 segment, proximal straight tubules • VPA, valproic acid

This version was published on August 1, 2009

Toxicologic Pathology, Vol. 37, No. 5, 629-643 (2009)
DOI: 10.1177/0192623309339605


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