Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat.
Renal ischemia results in both a profound fall in cellular ATP and a rapid induction of the 70 kD heat-shock protein family, HSP-70. The present studies examined the relationship between cellular ATP and induction of the stress response in renal cortex. Cellular ATP, continuously monitored by in vivo 31P-NMR spectroscopy, was reduced and maintained at specific, stable levels in renal cortex by partial aortic occlusion 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% preocclusion (control) levels. Reduction in cortical ATP levels to 35-50% preocclusion values resulted in HSF activation and low-level expression of inducible HSP-70 mRNA. Cellular ATP of 20-25% control values resulted in a greater level of HSF activation and subsequent HSP-70 mRNA elaboration. HSF was activated at the end of 15 min of total occlusion. The studies indicate that a 50% reduction in cellular ATP in the renal cortex must occur before the stress response is detectable, that reduction of ATP below 25% control levels produces a more vigorous response, and that reperfusion is not required for initiation of a heat-shock response in the kidney. Cellular ATP, or the metabolic consequences associated with ATP depletion, may be a threshold factor for initiation of a stress response in the kidney.
Van Why
S K
SK
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510.
Mann
A S
AS
Thulin
G
G
Zhu
X H
XH
Kashgarian
M
M
Siegel
N J
NJ
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003251:Constriction, Pathologic; D004247:DNA / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007511:Ischemia; D007672:Kidney Cortex / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000502:physiology*
D018840:HSP70 Heat-Shock Proteins; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D004247:DNA