Induction of heat shock protein 70 inhibits ischemic renal injury.
Induction of heat shock protein 70 inhibits ischemic renal injury.
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DOI：
10.1038/ki.2010.527
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发表时间：
2011-04
影响因子：
19.6
通讯作者：
Borkan SC
中科院分区：
文献类型：
--
作者：
Wang Z;Gall JM;Bonegio RG;Havasi A;Hunt CR;Sherman MY;Schwartz JH;Borkan SC
热休克蛋白70（Hsp 70）是一种有效的抗凋亡剂。在这里，我们测试了它是否直接调节肾细胞的存活和器官功能的模型，短暂的肾缺血Hsp 70敲除，杂合子和野生型小鼠。肾皮质Hsp 70含量与损伤后肾小管损伤、细胞凋亡和器官功能障碍呈负相关。在基因敲除小鼠中，缺血引起Akt和糖原合成酶激酶3-β（调节促凋亡蛋白Bax的激酶）活性的变化，增加Bax活性，并激活促凋亡蛋白酶caspase 3。由于这些变化在野生型小鼠中显著减少，我们测试了Hsp 70是否影响缺血诱导的细胞凋亡。Hsp 70诱导剂，香叶基香叶基丙酮，增加Hsp 70在杂合子和野生型小鼠的表达，并减少缺血性肾小管损伤和器官功能障碍。当在缺血后给药时，这种诱导剂也减少了野生型小鼠的肾小管损伤和器官衰竭，但没有保护基因敲除小鼠。与野生型小鼠相比，体外ATP耗竭导致从敲除中收获的原代近曲小管细胞中线粒体Bax积累和死亡更大，并改变了Akt特异性靶位点处Bax肽的丝氨酸磷酸化。相反，慢病毒介导的Hsp 70补充减少线粒体Bax的积累和拯救Hsp 70敲除细胞死亡。因此，在缺血性损伤之前或之后增加Hsp 70通过减轻急性肾损伤来保护肾功能。
Heat shock protein 70 (Hsp70) is a potent antiapoptotic agent. Here, we tested whether it directly regulates renal cell survival and organ function in a model of transient renal ischemia using Hsp70 knockout, heterozygous, and wild-type mice. The kidney cortical Hsp70 content inversely correlated with tubular injury, apoptosis, and organ dysfunction after injury. In knockout mice, ischemia caused changes in the activity of Akt and glycogen synthase kinase 3-β (kinases that regulate the proapoptotic protein Bax), increased active Bax, and activated the proapoptotic protease caspase 3. As these changes were significantly reduced in the wild-type mice, we tested whether Hsp70 influences ischemia-induced apoptosis. An Hsp70 inducer, geranylgeranylacetone, increased Hsp70 expression in heterozygous and wild-type mice, and reduced both ischemic tubular injury and organ dysfunction. When administered after ischemia, this inducer also decreased tubular injury and organ failure in wild-type mice but did not protect the knockout mice. ATP depletion in vitro caused greater mitochondrial Bax accumulation and death in primary proximal tubule cells harvested from knockout compared with wild-type mice and altered serine phosphorylation of a Bax peptide at the Akt-specific target site. In contrast, lentiviral-mediated Hsp70 repletion decreased mitochondrial Bax accumulation and rescued Hsp70 knockout cells from death. Thus, increasing Hsp70 either before or after ischemic injury preserves renal function by attenuating acute kidney injury.
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影响因子：
4.8
作者：
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