ToxSci Advance Access originally published online on September 8, 2005
Toxicological Sciences 2005 88(2):576-584; doi:10.1093/toxsci/kfi303
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Modulating the Endoplasmic Reticulum Stress Response with trans-4,5-Dihydroxy-1,2-Dithiane Prevents Chemically Induced Renal Injury In Vivo
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* Department of Chemistry, Clarkson University, Potsdam, New York; Toxicology and Drug Disposition, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46146; Renal Division, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Received June 15, 2005; accepted August 24, 2005
Agents that disrupt functions of the endoplasmic reticulum (ER) induce expression of ER stress-response genes including ER chaperones. Increased expression of the major ER chaperone, Grp78, protects cells, including renal epithelial cells, from chemically induced injury and death in vitro. In this study, we determined if pharmacological manipulation of the ER stress-response gene is an effective strategy to protect the kidney from chemical stress in vivo. Treatment with trans-4,5-dihydroxy-1,2-dithiane (DTTox), a novel inducer of ER stress proteins, stimulated a time-and dose-dependent increase in Grp78 expression in the kidney, but it did not cause detectable injury. Furthermore, prior treatment with DTTox protected the proximal tubular epithelium against a subsequent challenge with the nephrotoxicant S-(1,1,2,2,-tetrafluoroethyl)-L-cysteine (TFEC). In contrast, activating a heat shock response did not have a protective effect. Prior treatment with DTTox did not reduce covalent binding of radiolabeled reactive metabolites of 35S-TFEC to renal proteins, indicating that protection was not due to an effect on the metabolic activation of TFEC to the reactive metabolite(s) responsible for renal injury. Antisense grp78 expression in the renal epithelial cell line LLC-PK1 blocked the DTTox-induced Grp78 increase and ablated the protective effect against TFEC damage, indicating that the induction of grp78 expression and the ER stress response were critical for the protective effect of DTTox. These findings suggest that increased expression of Grp78 plays a major role in the protection of renal epithelial cells from reactive intermediate–induced chemical injury in vivo and that pharmacological manipulation is an effective strategy to prevent damage by some classes of nephrotoxicants.
Key Words: ER stress; Grp78; renal injury; nephrotoxicant; S-(1,1,2,2,-tetrafluoroethyl)-L-cysteine (TFEC); trans-4,5-dihydroxy-1,2-dithiane (DTTox).
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