Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy
Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy
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DOI：
10.1016/j.lfs.2009.11.022
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发表时间：
2010-01-16
期刊：
影响因子：
6.1
通讯作者：
Wang, Nai-Phog
中科院分区：
文献类型：
--
作者：
Yeh, Chung-Hsin;Hsu, Shih-Ping;Wang, Nai-Phog
目的：重复低氧预处理（RHP）可能通过低氧诱导因子lot（HIF-1 α）依赖的热休克蛋白70（HSP 70）途径对肾缺血/再灌注损伤提供比单一低氧预处理更有效的保护作用。我们用蛋白质印迹法评估了HIF-1 α、HSP 70、内质网应激蛋白GRP 78、半胱天冬酶12、Beclin-1和聚ADP核糖聚合酶（PARP）在肾脏的表达。通过末端转移酶dUTP缺口末端标记（TUNEL）、Beclin-1依赖性自噬和单核细胞/巨噬细胞（艾德-1）浸润测定肾细胞凋亡。肾功能测定采用血尿素氮（BUN）和血浆肌酐水平。HIF-1 α抑制剂和HSP 70的脱氧核糖核苷酸（DNA）或核糖核苷酸（RNA）干扰被用来评估它们在这个过程中的可能作用。关键发现：低氧预处理增强了肾HIF-1 α和HSP 70的表达，并且被HIF-1 α抑制剂YC-1以及磷脂酰肌醇3激酶（PI 3 K）/Akt抑制剂抑制。恢复常氧后，RHP组大鼠肾脏HSP 70蛋白水平可维持1周，而单纯低氧预处理组大鼠肾脏HSP 70蛋白水平在1天后下降。缺血/再灌注显著增加对照组大鼠肾脏TUNEL-凋亡、Beclin-1依赖性自噬、艾德-1浸润、GRP 78、caspase 12、Beclin-1、PARP和BUN的表达以及血浆肌酐水平。RHP显著降低所有缺血/再灌注增强参数。YC-1和槲皮素（HSP 70诱导的抑制剂）腹腔预处理可消除RHP诱导的保护作用。反义寡脱氧核苷酸或干扰RNA靶向热休克蛋白70废除了对缺氧/复氧诱导的氧化损伤RHP处理的近端tubules.Significance的保护：我们证明，RHP促进HIF-1 α依赖的热休克蛋白70信号转导，以减少肾缺血/再灌注损伤。(C)2009 Elsevier Inc. All rights reserved.
Aims: Repetitive hypoxic preconditioning (RHP) may provide more efficient protection than single hypoxic preconditioning against renal ischemia/reperfusion-induced injury via hypoxia-incluced factor lot (HIF-1 alpha)-dependent heat shock protein 70 (HSP70) pathways.Main methods: Wistar rats were subjected to intermittent hypoxic exposure (15 h/day), whereas controls were kept at sea level. We evaluated renal expression of HIF-1 alpha, HSP70, the endoplasmic reticulum stress protein GRP78, caspase 12, Beclin-1, and poly-(ADP-ribose)-polymerase (PARP) with western blotting. Renal apoptosis determined by terminal transferase dUTP nick end labeling (TUNEL), Beclin-1 -dependent autophagy, and monocyte/macrophage (ED-1) infiltration were evaluated by immunocytochemistry. Renal function was determined with blood urea nitrogen (BUN) and plasma creatinine levels. HIF-1 alpha inhibitors and Deoxyribonucleotide (DNA) or Ribonucleotide (RNA) interference of HSP70 were used to evaluate their possible roles in this process.Key findings: Renal HIF-1 alpha and HSP70 expression were enhanced by hypoxic preconditioning and inhibited by the HIF-1 alpha inhibitor, YC-1, as well as phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors. After the return to normoxia, renal HSP70 protein levels were maintained for one week in the RHP group, but they decayed after one day in the single hypoxic preconditioning group. Ischemia/reperfusion significantly increased renal TUNEL-apoptosis, Beclin-1 -dependent autophagy, ED-1 infiltration, expression of GRP78, caspase 12, Beclin-1, PARP, and BUN and plasma creatinine levels in control rats. RHP significantly decreased all ischemia/reperfusion-enhanced parameters. Intraperitoneal pretreatment with YC-1 and quercetin (an inhibitor of HSP70 induction) eliminated RHP-induced protection. Anti-sense oligodeoxyribonucleotides or interference RNA targeting HSP70 abrogated the protection against hypoxia/reoxygenation-induced oxidative injury in RHP-treated proximal tubules.Significance: We demonstrate that RHP promotes HIF-1 alpha-dependent HSP70 signaling to reduce renal ischemia/reperfusion injury. (C) 2009 Elsevier Inc. All rights reserved.