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Immunolocalization of Kim-1, RPA-1, and RPA-2 in Kidney of Gentamicin-, Mercury-, or Chromium-Treated Rats: Relationship to Renal Distributions 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 Biotrin International 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, MD, MS, 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; e-mail:jun.zhang{at}fda.hhs.gov.

Immunohistochemical studies for kidney injury molecule-1 (Kim-1), renal papillary antigen-1 (RPA-1), and renal papillary antigen-2 (RPA-2) were conducted to explore their relationship to inducible nitric oxide synthase (iNOS) and nitrotyrosine expression. Male Sprague-Dawley rats were exposed to gentamicin (100 mg/kg/day Gen, sc, for 3 days), mercury (0.25 mg Hg/kg, iv, single dose), or chromium (5 mg Cr/kg, sc, single dose) and kidney tissue was examined 24 hours or 72 hours after the last dose of the nephrotoxicant. Another group of kidneys was evaluated 24 hours after rats were administered 3 daily doses (50, 100, 150, 200, or 300 mg/kg/day) of Gen. Gen- and Cr-treated rats exhibited increased immunoreactivity of Kim-1, RPA-1, and RPA-2 largely in the S1/S2 segments and to a lesser extent in the S3 segments of the proximal tubule of the kidney, whereas Hg-treated rats showed increased immunoreactivity of Kim-1, RPA-1, and RPA-2 in the S3 segments. Up-regulation of Kim-1, RPA-1, and RPA-2 expression correlated with injured tubular epithelial cells and also correlated with immunoreactivity of iNOS and nitrotyrosine. It is possible that iNOS activation with nitrotyrosine production in injured nephron segments may be involved in the induction of Kim-1, RPA-1, and RPA-2 following exposure to nephrotoxicants.

Key Words: chromium • gentamicin • Kim-1 (kidney injury molecule-1) • mercury • nitrotyrosine • RPA-1 (renal papillary antigen-1) • RPA-2 (renal papillary antigen-2)

Abbreviations: CD, collecting ducts • Cr, chromium (K₂Cr₂O₇) • DCT, distal convoluted tubule • Gen, gentamicin sulfate • Hg, mercury (HgCl₂) • iNOS, inducible nitric oxide synthase • Kim-1, kidney injury molecule-1 • LH, loop of Henle • mAb, monoclonal antibody • NO, nitric oxide • pAb, polyclonal antibody • RPA-1, renal papillary antigen-1 • RPA-2, renal papillary antigen-2 • S1/S2, segments and S3 segment, the S1 & S2 segments of proximal convoluted tubules and the S3 segment of proximal straight tubule

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