Relationship between stress protein induction in rat kidney by mercuric chloride and nephrotoxicity.
Adverse environmental stimuli increase the synthesis of a class of proteins referred to as stress proteins. The effect of mercuric chloride, a model nephrotoxin, on protein synthesis in male rat kidney has been evaluated. Renal slices from exposed rats were incubated with [35S]methionine for 1 hr and subjected to SDS-PAGE, after which 35S-labeled proteins were detected by autoradiography. Enhanced de novo synthesis of 70- and 90-kDa relative molecular mass (M(r)) proteins were detected 2 hr after exposure to 1 mg Hg/kg, with maximum activity occurring at 4-8 hr. By 16 hr postinjection, synthesis of these two proteins had decreased. Dose-related increases in synthesis of these proteins, and of a 110-kDa protein, were observed 4 hr after i.v. injection of 0.25, 0.5, and 1.0 mg Hg/kg, with concomitant inhibition of synthesis of proteins of M(r) 38 and 68 kDa. At a dose of 1 mg/kg, kidney proximal tubules exhibited progressive degenerative changes from 4 to 24 hr. A functional deficit, decreased uptake of [para-3H]aminohippurate into renal slices, was not observed until 16 hr after i.v. injection of 1 mg/kg. No significant histopathologic changes were observed in kidneys 4 hr after treatment with 0.25 or 0.5 mg Hg/kg, iv. No changes in liver protein synthesis were apparent until 16-24 hr, where an increase in the 70- and 90-kDa proteins was observed. A concomitant increase in plasma sorbitol dehydrogenase activity occurred at 16-24 hr; however, there was no histopathological evidence of liver injury. The 72-kDa inducible member of the 70-kDa stress protein family and the 88-kDa member of the 90-kDa protein family were detected by immunoblotting techniques using monoclonal antibodies. The data demonstrate that Hg induces alterations in the expression of renal gene products in vivo as evidenced by enhanced stress protein synthesis and inhibition of synthesis of constitutive proteins. These changes in renal protein synthesis preceded overt renal injury, occurring in the early stages of nephropathy. Altered patterns of stress protein synthesis appeared to be target organ specific. The data suggest that altered protein synthesis patterns may serve as biomarkers of renal injury.
Goering
P L
PL
Division of Life Sciences, Food and Drug Administration, Rockville, Maryland 20857.
Fisher
B R
BR
Chaudhary
P P
PP
Dick
C A
CA
D000818:Animals; D001345:Autoradiography; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008627:Mercuric Chloride / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D006360:Heat-Shock Proteins; D008627:Mercuric Chloride