Induction of clusterin in acute and chronic oxidative renal disease in the rat and its dissociation from cell injury.
BACKGROUND: Clusterin is a glycoprotein incriminated in diverse biologic processes including complement regulation, cell death, and tissue remodelling. Induction of clusterin occurs in renal and other tissue injuries. EXPERIMENTAL DESIGN: The purpose of this study was to determine the effect of prooxidant states, one acute (glycerol-induced acute renal failure) and the other chronic (vitamin E and selenium deficiency) on renal clusterin expression, and to attempt to delineate the signals which in these in vivo models can elicit expression of clusterin in vitro. RESULTS: In glycerol-induced acute renal failure, a model of rhabdomyolysis, clusterin mRNA was markedly increased 24 hours after injection of glycerol (control 97 +/- 21 versus glycerol 3644 +/- 134 optical density units; p < 0.001). Immunohistochemical clusterin was also increased in glycerol-treated rats with tubules in both cortex and medulla staining for clusterin. In vitamin E and selenium deficiency, clusterin mRNA was increased 9 weeks after initiation of the deficient diet (control 97 +/- 13 versus deficient 1137 +/- 403 optical density units; p < 0.04) as were the number of tubules staining for clusterin. Since renal injury is instigated in the glycerol model by muscle damage, we tested the effect of muscle extract on clusterin expression in vitro. A homogenate of skeletal muscle induced clusterin mRNA and this induction was not associated with disruption of cell membranes and was not inhibited by cycloheximide treatment, but was blocked by actinomycin D. Since increased generation of hydrogen peroxide is a pivotal biochemical lesion in both in vivo models, we tested the effect of peroxide to induce clusterin in vitro; no such induction occurred. CONCLUSIONS: Renal tubular clusterin expression was increased in both acute glycerol-induced renal failure and chronic vitamin E and selenium deficiency, two in vivo models of oxidant injury to the kidney. In vitro induction of clusterin can occur and can be dissociated from cell injury.
Nath, KA; Dvergsten, J; Correa-Rotter, R; Hostetter, TH; Manivel, JC; Rosenberg, ME
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