ACTIVATION OF HEAT-SHOCK TRANSCRIPTION FACTOR BY GRADED REDUCTIONS INRENAL ATP, IN-VIVO, IN THE RAT

Renal ischemia results in both a profound fall in cellular ATP and a r apid induction of the 70 kD heat-shock protein family, HSP-70. The pre sent studies examined the relationship between cellular ATP and induct ion of the stress response in renal cortex. Cellular ATP, continuously monitored by in vivo P-31-NMR spectroscopy, was reduced and maintaine d at specific, stable levels in renal cortex by partial aortic occlusi on for 45 min. Activation of heat-shock transcription factor (HSF) was detected by gel retardation assay and transcription was confirmed by Northern analysis. Activation of HSF was not present, and HSP-70 mRNA induction did not occur when ATP levels were maintained above 60% preo cclusion (control) levels. Reduction in cortical ATP Levels to 35-50% preocclusion values resulted in HSF activation and low-level expressio n of inducible HSP-70 mRNA. Cellular ATP of 20-25% control values resu lted in a greater level of HSF activation and subsequent HSP-70 mRNA e laboration. HSF was activated at the end of 15 min of total occlusion. The studies indicate that a 50% reduction in cellular ATP in the rena l cortex must occur before the stress response is detectable, that red uction of ATP below 25% control levels produces a more vigorous respon se, and that reperfusion is not required for initiation of a heat-shoc k response in the kidney. Cellular ATP, or the metabolic consequences associated with ATP depletion, may be a threshold factor for initiatio n of a stress response in the kidney.