Heat shock proteins and acquired resistance to uranium nephrotoxicity.
Previous studies have demonstrated that prior exposures to uranium can produce acquired resistance to uranium nephrotoxicity. In this study, the potential role for heat shock proteins (Hsps) in acquired resistance to uranium nephrotoxicity was explored. Pretreatment of male Sprague-Dawley rats with a conditioning dose of uranyl acetate (5 mg/kg, i.p.) was found to diminish the severity of proximal convoluted tubule necrosis and azotemia produced by a subsequent, higher uranyl acetate dose (10 mg/kg, i.p., 10 days after the conditioning dose). Kidney homogenates from rats euthanized at the end of the conditioning period were found to contain elevated levels of Hsp25, Hsp32, and Hsp70i, but not Hsc70. Immunochemical staining of renal sections for Hsp25 and Hsp70i revealed that these proteins were prominently expressed in tubular epithelial cells in uranyl acetate pretreated animals. Morphological characteristics and staining for proliferating cell nuclear antigen (PCNA) indicated that the cells expressing high levels of Hsps were regenerating. In RK3E and LLC-PK1 renal epithelial cells in culture, Hsp induction by thermal pretreatment did not afford protection from uranyl acetate cytotoxicity. Further, treatment of RK3E and LLC-PK1 cells with uranyl acetate did not result in induction of Hsps, as occurs with other nephrotoxic heavy metals. These observations suggest that while stress proteins are elevated in acquired resistance to uranyl acetate in vivo, they are not responsible for diminished uranium nephrotoxicity but are an epiphenomenon of tubular epithelial regeneration.
Tolson
J Keith
JK
Department of Pharmacology and Therapeutics, Center for Environmental and Human Toxicology, J. Hillis Miller Health Science Center, University of Florida, P.O. Box 110885, Gainesville, FL 32611, USA.
Roberts
Stephen M
SM
Jortner
Bernard
B
Pomeroy
Melinda
M
Barber
David S
DS
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009942:Organometallic Compounds / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D006360:Heat-Shock Proteins; D009942:Organometallic Compounds; D018809:Proliferating Cell Nuclear Antigen; C005460:uranyl acetate