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首页> 外文期刊>Life sciences >Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy.
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Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy.

机译：缺氧预处理增强了HIF-α依赖性HSP70信号传导，以减少缺血性肾衰竭引起的肾小管凋亡和自噬。

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AIMS: Repetitive hypoxic preconditioning (RHP) may provide more efficient protection than single hypoxic preconditioning against renal ischemia/reperfusion-induced injury via hypoxia-induced factor 1alpha (HIF-1alpha)-dependent heat shock protein 70 (HSP70) pathways. MAIN METHODS: Wistar rats were subjected to intermittent hypoxic exposure (15h/day), whereas controls were kept at sea level. We evaluated renal expression of HIF-1alpha, 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-1alpha inhibitors and Deoxyribonucleotide (DNA) or Ribonucleotide (RNA) interference of HSP70 were used to evaluate their possible roles in this process. KEY FINDINGS: Renal HIF-1alpha and HSP70 expression were enhanced by hypoxic preconditioning and inhibited by the HIF-1alpha 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-1alpha-dependent HSP70 signaling to reduce renal ischemia/reperfusion injury.
机译：目的：重复性低氧预处理（RHP）可以通过缺氧诱导的因子1α（HIF-1alpha）依赖性热休克蛋白70（HSP70）途径提供比单一低氧预处理更有效的针对肾脏缺血/再灌注诱导的损伤的保护。主要方法：Wistar大鼠间歇性低氧暴露（15h /天），而对照组保持在海平面。我们用western blotting评估了HIF-1alpha，HSP70，内质网应激蛋白GRP78，胱天蛋白酶12，Beclin-1和聚-（ADP-核糖）-聚合酶（PARP）的肾脏表达。通过免疫细胞化学评估通过末端转移酶dUTP缺口末端标记（TUNEL），Beclin-1依赖性自噬和单核/巨噬细胞（ED-1）浸润确定的肾细胞凋亡。肾功能由血尿素氮（BUN）和血浆肌酐水平确定。使用HIF-1alpha抑制剂和HSP70的脱氧核糖核苷酸（DNA）或核糖核苷酸（RNA）干扰来评估其在此过程中的可能作用。主要发现：缺氧预处理可增强肾脏HIF-1alpha和HSP70的表达，并被HIF-1alpha抑制剂YC-1和磷脂酰肌醇3-激酶（PI3K）/ Akt抑制剂抑制。恢复到正常氧水平后，RHP组的肾脏HSP70蛋白水平维持了1周，但在单氧预处理组中，它们在一天后就下降了。缺血/再灌注显着增加了对照组大鼠的肾TUNEL细胞凋亡，Beclin-1依赖性自噬，ED-1浸润，GRP78，胱天蛋白酶12，Beclin-1，PARP和BUN的表达以及血浆肌酐水平。 RHP显着降低了所有缺血/再灌注增强的参数。 YC-1和槲皮素（HSP70诱导抑制剂）的腹膜内预处理消除了RHP诱导的保护作用。针对HSP70的反义寡聚脱氧核糖核苷酸或干扰RNA废除了RHP处理的近端小管对缺氧/复氧诱导的氧化损伤的保护作用。意义：我们证明RHP促进HIF-1alpha依赖性HSP70信号传导，以减少肾缺血/再灌注损伤。

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