Reduced tolerance of immature renal tubules to anoxia by HSF-1 decoy.
Immature animals demonstrate an amplified heat shock response following a variety of insults compared with that seen in mature animals (M). The potential role of the heat shock response in modulating immature tolerance to injury was compared between rat pups, 10 postnatal days of age (P10), and M. Baseline levels of the heat shock transcription factor (HSF-1) were substantially elevated in P10 compared with M animals. In uninjured P10 pups, HSF-1 level was comparable to that of M animals subjected to 45 min of ischemia. As anticipated, the integrity of suspensions of tubules exposed to anoxia was preserved in P10 animals (23% LDH release) compared with M (40%), P < 0.01. The effect of targeted inhibition of HSF-1 on tubular integrity was studied using a cyclic oligonucleotide decoy. The HSF-1 decoy increased the severity of anoxic injury in P10 pups to a level comparable with M animals. LDH release was 33% in decoy-treated P10 tubules compared with 40% in M. When P10 tubules were treated with scrambled decoy, resistance to anoxia remained intact (24%). The increased vulnerability of the tubular suspension to injury was specific to the HSF-1 decoy and proportional to the dose of decoy applied. This study demonstrates maturation in the abundance of HSF-1 in the immature rat kidney. The loss of resistance of immature tubules to anoxia with specific inhibition of HSF-1 may be due to its effect on the heat shock response or other signaling pathways of critical pathobiological importance in renal cell injury.
Department of Pediatrics, Yale University, New Haven, CT 06520-8064, USA.
Rajasree
R
Sreedharan
Michael
M
Riordan
Shirley
S
Wang
Gunilla
G
Thulin
Michael
M
Kashgarian
Norman J
NJ
Siegel
D000222:Adaptation, Physiological; D000818:Animals; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D000076249:Heat Shock Transcription Factors; D006358:Hot Temperature / Q000009:adverse effects*; D007684:Kidney Tubules / Q000473:pathology / Q000502:physiology*; D009841:Oligonucleotides; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D009841:Oligonucleotides; D014157:Transcription Factors