Submitted on August 16, 2004
Accepted on September 28, 2004
Reduced tolerance of immature renal tubules to anoxia by HSF-1 decoy
Rajasree Sreedharan1, Michael Riordan1, Shirley Wang2, Gunilla Thulin1, Michael Kashgarian3, and Norman J. Siegel1*
1 Department of Pediatrics, Yale University, New Haven, CT, USA
2 Magnetic Resonance Research Center, Yale University, New Haven, CT, USA
3 Department of Pathology, Yale University, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: norman.siegel{at}yale.edu.
Immature animals demonstrate an amplified heat shock response following a variety of insults in comparison to that seen in mature animals. The potential role of the heat shock response in modulating immature tolerance to injury was compared between rat pups, 10 post natal days of age (P10), and mature animals (M). Baseline levels of the heat shock transcription factor, HSF-1, were substantially elevated in P10 compared to M animals. In uninjured P10 pups HSF-1 level was comparable to that of M animals subjected to 45 minutes of ischemia. As anticipated, the integrity of suspensions of tubules exposed to anoxia was preserved in P10 animals (23% LDH release) compared to M (40%) - p<0.01. The effect of targeted inhibition of HSF-1 on tubular integrity was studied using a cyclic oligonucleotide decoy. 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 to 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 the 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.
