Sreedharan Rajasree, Riordan Michael, Wang Shirley, Thulin Gunilla, Kashgarian Michael, Siegel Norman J
Department of Pediatrics, Yale University, New Haven, CT 06520-8064, USA.
Am J Physiol Renal Physiol. 2005 Feb;288(2):F322-6. doi: 10.1152/ajprenal.00307.2004. Epub 2004 Oct 5.
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.
与成熟动物（M）相比，未成熟动物在遭受各种损伤后会表现出放大的热休克反应。比较了10日龄（P10）的幼鼠和M动物热休克反应在调节未成熟动物对损伤耐受性中的潜在作用。与M动物相比，P10幼鼠热休克转录因子（HSF-1）的基线水平显著升高。在未受伤的P10幼鼠中，HSF-1水平与经历45分钟缺血的M动物相当。正如预期的那样，与M动物（40%）相比，暴露于缺氧环境的肾小管悬浮液在P10动物中保持完整（乳酸脱氢酶释放率为23%），P<0.01。使用环状寡核苷酸诱饵研究了靶向抑制HSF-1对肾小管完整性的影响。HSF-1诱饵使P10幼鼠缺氧损伤的严重程度增加到与M动物相当的水平。诱饵处理的P10肾小管中乳酸脱氢酶释放率为33%，而M动物为40%。当用乱序诱饵处理P10肾小管时，对缺氧的抵抗力保持完整（2�%）。肾小管悬浮液对损伤的易感性增加是HSF-1诱饵特有的，并且与所应用诱饵的剂量成比例。本研究证明了未成熟大鼠肾脏中HSF-1丰度的成熟。特异性抑制HSF-1导致未成熟肾小管对缺氧抵抗力的丧失可能是由于其对热休克反应或肾细胞损伤中关键病理生物学重要性的其他信号通路的影响。
