Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat

Scott K. Van Why, Andrea S. Mann, Gunilla Thulin, Xiao Hong Zhu, Michael Kashgarian, Norman J. Siegel

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1518-1523
Number of pages6
JournalJournal of Clinical Investigation
Volume94
Issue number4
DOIs
StatePublished - Oct 1994

Keywords

  • adenosine triphosphate
  • heat-shock proteins
  • ischemia
  • kidney
  • transcription factors

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