HDAC抑制剂SAHA调控自噬减轻缺血再灌注急性肾损伤的作用和机制研究

Ischemia-reperfusion induced acute kidney injury (IR-AKI) is a common disorder with a high risk of mortality. There is no specific pharmacological therapy proven to effectively treat AKI. Recent studies demonstrated that histone deacetylase inhibitors (HDACis) are effective at treating multiple chronic kidney diseases. Suberoyla-nilide hydroxamic acid (SAHA) is a pan-histone deacetylase inhibitor. The role of SAHA in treating IR-AKI and the underlying molecular mechanisms are still no clear. Autophagy is a conserved dynamic catabolic process. There have been studies showed the renoprotective role of tubular cell autophagy in acute kidney injury. Our previous studies showed that SAHA induces autophagy of renal tubular cell (HK-2 cells), as evidenced by increased mRNA expression of Beclin-1 and LC3-II and decreased protein level of p62. We hypothesize that SAHA attenuates IR-AKI by inducing renal tubular cell autophagy. Thus we will investigate the effect of SAHA on autophagy and FOXO1-MTOR signal transduction pathway from both normal HK-2 cell culture and ischemia/reperfusion model, meanwhile verify the effectiveness of SAHA in treating IR-AKI. The aim of this project is to prove that SAHA induces autophagy through FOXO1-MTOR dependent pathways in tubular cell, and then alleviates IR-AKI. Hopefully we will shed new light in treating acute kidney injury.

缺血再灌注急性肾损伤(IR-AKI)是常见的临床急重症，目前尚无有效药物治疗。近年相关研究报道了HDAC抑制剂(HDACi)在多种慢性肾脏疾病中的治疗作用，SAHA是非选择性HDACi，其在IR-AKI中的作用以及机制尚未阐明。自噬是机体重要的代谢机制，已有研究发现肾小管上皮细胞的自噬在IR-AKI中起着重要的保护作用。我们前期研究发现SAHA作用于HK-2细胞后自噬标记物Beclin-1和LC3-II的基因转录水平增加，p62蛋白水平下降，提示SAHA促进肾小管上皮细胞自噬。据此我们提出SAHA通过调节自噬减轻IR-AKI的假设。本研究拟通过在正常环境和模拟缺血再灌注下探讨SAHA对肾小管上皮细胞自噬以及对FOXO1-MTOR信号通路的作用，观察在IR-AKI中SAHA对肾脏的保护作用，证明SAHA通过FOXO1-MTOR信号通路诱导自噬缓解IR-AKI，为治疗IR-AKI提供新思路。

缺血再灌注急性肾损伤(IR-AKI)是常见的临床急重症，目前尚无有效药物治疗。已有相关研究报道了HDAC抑制剂(HDACi)在多种慢性肾脏疾病中的治疗作用，SAHA是非选择性HDACi，其在IR-AKI中的作用以及机制尚未阐明。自噬是机体重要的代谢机制，已有研究发现肾小管上皮细胞的自噬在IR-AKI中起着重要的保护作用。我们前期研究发现SAHA作用于HK-2细胞后自噬标记物Beclin-1和LC3-II的基因转录水平增加，p62蛋白水平下降，提示SAHA促进肾小管上皮细胞自噬。据此我们提出SAHA通过调节自噬减轻IR-AKI的假设。本研究拟通过在正常环境和模拟缺血再灌注下探讨SAHA对肾小管上皮细胞自噬以及对FOXO1-MTOR信号通路的作用，观察在IR-AKI中SAHA对肾脏的保护作用，证明SAHA通过FOXO1-mTOR信号通路诱导自噬缓解IR-AKI，为治疗IR-AKI提供新思路。