FOXO1 inhibition prevents renal ischemia-reperfusion injury via cAMP-response element binding protein/PPAR-γ coactivator-1α-mediated mitochondrial biogenesis
FOXO1 inhibition prevents renal ischemia-reperfusion injury via cAMP-response element binding protein/PPAR-γ coactivator-1α-mediated mitochondrial biogenesis
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DOI：
10.1111/bph.14878
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发表时间：
2019-12-23
影响因子：
7.3
通讯作者：
Tie, Lu
中科院分区：
文献类型：
--
作者：
Wang, Di;Wang, Yanqing;Tie, Lu
背景与目的越来越多的证据表明，靶向线粒体动力学和生物发生能加速肾缺血再灌注(I/R)损伤的恢复，但其潜在机制仍不清楚。转录因子Forkhead box O1(FOXO1)是线粒体动态平衡的关键调节因子，在肾脏疾病的发展中起着重要的病理作用。实验方法采用小鼠肾I/R损伤模型和人肾小管上皮细胞缺氧/复氧(H/R)损伤模型。关键结果I/R损伤前肾脏FOXO1表达上调，损伤前应用FOXO1选择性抑制剂AS1842856可降低损伤后血清尿素氮、血肌酐和肾小管损伤评分。AS1842856治疗还能改善I/R损伤小鼠的肾功能，提高小鼠的存活率。AS1842856在体内和体外均能减少线粒体介导的细胞凋亡，抑制线粒体ROS的过量产生，促进ATP的恢复。此外，FOXO1抑制促进了线粒体的生物发生并抑制了有丝分裂。线粒体生物发生的主要调节因子PPAR-γ共激活因子1α(PGC-1α)的表达在I/R和H/R损伤中均下调，FOXO1抑制可消除这种下调。综合生物信息学分析和免疫共沉淀实验证实，FOXO1通过与cAMP反应元件结合蛋白(CREB)竞争其与转录共激活物CREBBP/EP300(/)的结合来抑制PGC-1α的转录。结论FOXO1在维持肾小管上皮细胞线粒体功能中起重要作用，FOXO1可作为药物干预肾I/R损伤的治疗靶点。
Background and Purpose Growing evidence indicates targeting mitochondrial dynamics and biogenesis could accelerate recovery from renal ischemia-reperfusion (I/R) injury, but the underlying mechanisms remain elusive. Transcription factor forkhead box O1 (FOXO1) is a key regulator of mitochondrial homeostasis and plays a pathological role in the progression of renal disease. Experimental Approach A mouse model of renal I/R injury and a hypoxia/reoxygenation (H/R) injury model for human renal tubular epithelial cells were used. Key Results I/R injury up-regulated renal expression of FOXO1 and treatment with FOXO1-selective inhibitor AS1842856 prior to I/R injury decreased serum urea nitrogen, serum creatinine and the tubular damage score after injury. Post-I/R injury AS1842856 treatment could also ameliorate renal function and improve the survival rate of mice following injury. AS1842856 administration reduced mitochondrial-mediated apoptosis, suppressed the overproduction of mitochondrial ROS and accelerated recovery of ATP both in vivo and in vitro. Additionally, FOXO1 inhibition improved mitochondrial biogenesis and suppressed mitophagy. Expression of PPAR-gamma coactivator 1 alpha (PGC-1 alpha), a master regulator of mitochondrial biogenesis, was down-regulated in both I/R and H/R injury, which could be abrogated by FOXO1 inhibition. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that FOXO1 inhibited PGC-1 alpha transcription by competing with cAMP-response element binding protein (CREB) for its binding to transcriptional coactivators CREBBP/EP300 (/). Conclusion and Implications These findings suggested that FOXO1 was critical to maintain mitochondrial function in renal tubular epithelial cells and FOXO1 may serve as a therapeutic target for pharmacological intervention in renal I/R injury.