Mitochondrial Biogenesis Promotes Recovery from Oxidant Injury

描述（由申请人提供）：该项目的目标是确定加速急性器官衰竭恢复的治疗方法。由缺血/再灌注（I/R）、药物、毒物和创伤引起的细胞损伤和死亡可导致包括肾脏在内的许多器官衰竭。线粒体功能障碍是这些损伤的常见后果，也是细胞损伤和死亡的主要机制。急性肾损伤（AKI）领域的大多数研究都集中在引发肾功能障碍的事件上，但缺乏治疗药物。这表明，更成功的治疗方法需要检查新的靶点，并专注于加速AKI的恢复。我们最近发现，双侧肾I/R诱导AKI的小鼠和肌红蛋白尿AKI的大鼠在损伤后24小时血清肌酐升高，并在损伤后6天部分恢复。线粒体电子传递链和ATP合成蛋白在损伤后24小时被耗尽，并且在6天内没有恢复，表明AKI后线粒体功能持续中断。因此，我们建议增加线粒体生物发生（MB）的治疗方法将促进AKI的恢复。作为我们药物发现项目的一部分，我们发现福莫特罗是一种特异性的长效b2-肾上腺素能受体激动剂（b2-AR），是肾近端小管细胞（RPTC）中一种有效的MB诱导剂。福莫特罗是fda批准的用于治疗哮喘的药物。进一步的研究表明，福莫特罗在低剂量下诱导小鼠肾脏MB。然而，福莫特罗诱导MB的信号通路尚未被阐明。最后，初步研究表明，在I/R后24小时，当肾功能建立时，给予福莫特罗可以加速[线粒体和]肾功能的恢复。我们假设福莫特罗通过b2-AR诱导MB，福莫特罗加速I/R后小鼠[线粒体和]肾功能的恢复。为了解决这一假设，我们提出以下具体目标：1)阐明福莫特罗诱导的RPTC中MB的信号通路[以及RPTC氧化损伤后]，2)确定福莫特罗诱导的小鼠MB的疗效、效力和机制，3)阐明福莫特罗对肾I/ r诱导的AKI后线粒体和肾功能恢复的影响。这些实验的成功完成将通过以下途径推进该领域的发展：1)确定通过b2-AR诱导MB的精确信号通路；2)证明刺激线粒体功能的恢复可加速肾功能的恢复；3)为AKI提供快速临床可翻译的治疗方法。

DESCRIPTION (provided by applicant): The goal of this project is to identify therapeutics that accelerate the recovery from acute organ failure. Cell injury and death induced by ischemia/reperfusion (I/R), drugs, toxicants, and trauma lead to failure of many organs, including the kidney. Mitochondrial dysfunction is a common consequence of these insults and a major mechanism of cell injury and death. The majority of research in the field of acute kidney injury (AKI) has focused on the events that initiate renal dysfunction, but therapeutic agents are lacking. This suggests that more successful therapies require the examination of new targets and a focus on accelerating recovery from AKI. We recently determined that mice subjected to bilateral renal I/R induced AKI and rats subjected to myoglobinuric AKI had elevated serum creatinine 24 h after injury which partially recovered over six days post- injury. Mitochondrial electron transport chain and ATP synthesis proteins were depleted 24 h after injury and did not recover over six days, revealing persistent disruption of mitochondrial function after AKI. Consequently, we propose that therapeutics that increase mitochondrial biogenesis (MB) will promote recovery from AKI. As part of our drug discovery program to identify drugs that induce MB we identified formoterol, a specific long- acting b2-adrenergic receptor agonist (b2-AR), was a potent and efficacious inducer of MB in renal proximal tubular cells (RPTC). Formoterol is a FDA-approved drug used to treat asthma. Additional studies revealed that formoterol induced MB in the kidneys of mice at a low dose. However, the signaling pathway(s) responsible for formoterol-induced MB has not been elucidated. Finally, preliminary studies demonstrated that mice treated with formoterol 24 h after I/R, when renal dysfunction is established, accelerated recovery of [mitochondrial and] renal function. We hypothesize that formoterol induces MB through the b2-AR and that formoterol accelerates recovery of [mitochondrial and] renal function following I/R in mice. To address this hypothesis we propose the following Specific Aims: 1) Elucidate the signaling pathway(s) of formoterol- induced MB in RPTC [and following oxidant injury in RPTC], 2) Determine efficacy, potency and mechanism of formoterol-induced MB in mice, and 3) Elucidate the effects of formoterol on the recovery of mitochondrial and renal function following renal I/R-induced AKI in vivo. Successful completion of these experiments will advance the field by 1) identifying the precise signaling pathway that induces MB through b2-AR, 2) demonstrating that stimulating the recovery of mitochondrial function results in the acceleration of recovery of renal function, and 3) providing a rapidly clinically translatable treatment for AKI.