5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury

5-HT 刺激线粒体生物发生和急性肾损伤

• 批准号: 8391608
• 负责人: Rick G Schnellmann
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391608
• 关键词: ATP Synthesis Pathway; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adipose tissue; Agonist; Biochemical; Biogenesis; Biological; Brain; Cell Death; Cell Survival; Cell physiology; Cells; Couples; Failure; Gene Expression; Goals; HTR2A gene; Heart; Human; Injury; Ischemia; Kidney; Lead; Liver; Measures; Mediating; Mediator of activation protein; Messenger RNA; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Molecular; Mus; Natural regeneration; Nuclear; Organ; Organ Survival; Organ failure; Oryctolagus cuniculus; Oxidants; Oxidative Stress; PPAR gamma; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Process; Production; Public Health; Rattus; Receptor Activation; Recovery; Renal function; Reperfusion Therapy; Respiration; Reverse Transcriptase Polymerase Chain Reaction; Serotonin; Signal Pathway; Signal Transduction Pathway; Testing; Trauma; Tubular formation; abstracting; cell injury; dimethoxy-4-indophenyl-2-aminopropane; effective therapy; in vivo; in vivo Model; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; overexpression; public health relevance; receptor; repaired; toxicant

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to identify pharmacological treatments for acute organ failure. Cell injury and death induced by oxidative stress occur during ischemia/reperfusion (I/R), leading to failure of different organs such as heart, brain, liver and kidneys. I/R results in mitochondrial dysfunction, a major mechanism for cell injury and death via enhanced oxidant production and decreased ATP synthesis. Furthermore, oxidative stress and mitochondrial dysfunction is often the mediator of drug-, toxicant-, and trauma-induced cell death. Unfortunately, there are no truly effective therapies that can promote cell and organ repair/regeneration, and recovery of organ function following injury. Cells replace old and dysfunctional mitochondria through mitochondrial biogenesis. Peroxisome proliferator-activated receptor gamma coactivator-11 (PGC-11) is generally thought to be the master regulator of mitochondrial biogenesis in adipose tissue, heart, and liver, and we have shown that PGC-11 mediates mitochondrial biogenesis in renal proximal tubular cells (RPTC). In addition, we recently showed that over- expression of PGC-11 causes mitochondrial biogenesis in RPTC and that increasing mitochondrial biogenesis after oxidant injury accelerated recovery of mitochondrial and cellular functions. These exciting results support the hypothesis that post-injury mitochondrial biogenesis may be efficacious in stimulating cell and organ repair/regeneration. We discovered that the 5-hydroxytryptamine type 2 receptor (5-HT2) agonist, 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI), produced mitochondrial biogenesis. RT-PCR analysis of mRNA isolated from RPTC confirmed the expression of 5-HT2 receptor subtypes 5-HT2A, 5-HT2B and 5-HT2C in humans, rabbits, rats and mice. These results demonstrate that 5-HT2 receptors are found in RPTC in multiple species, and that activation of the 5-HT2 receptors causes mitochondrial biogenesis. Finally, treatment of RPTC with DOI after oxidant injury accelerated the return of mitochondrial and cellular functions compared to oxidant injury alone. In addition, preliminary studies in vivo revealed that DOI produces mitochondrial biogenesis in the mouse kidney [and accelerates the recovery of renal function following I/R.] These studies support our overall hypothesis that a specific 5-HT2 receptor mediates mitochondrial biogenesis and accelerates the recovery of renal function following acute kidney injury (AKI). The following Specific Aims will test this hypothesis: 1) Specific Aim 1: Identify the specific 5-HT2 receptor subtype responsible for mitochondrial biogenesis in RPTC, 2) Specific Aim 2: Elucidate the signal transduction pathway that couples 5-HT2 receptor activation to mitochondrial biogenesis in RPTC, and 3) Specific Aim 3: Determine the efficacy of specific 5-HT2 receptor agonists on mitochondrial biogenesis in vivo and the recovery of renal function in a mouse model of renal I/R. These studies will examine a new target, mitochondrial biogenesis, and a novel pathway of mitochondrial biogenesis, 5-HT2 receptors, in the treatment of acute organ injury, specifically AKI, using cellular and in vivo models. We will use a combination of molecular biological, biochemical, and pharmacological approaches to complete the aims identified above. Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic situations.

描述(由申请人提供)： 项目摘要/摘要该项目的长期目标是确定急性器官衰竭的药物治疗方法。在缺血/再灌注(I/R)过程中，氧化应激导致细胞损伤和死亡，导致心、脑、肝、肾等不同器官衰竭。I/R导致线粒体功能障碍，这是细胞损伤和死亡的主要机制，它通过增加氧化剂的产生和减少ATP的合成来实现。此外，氧化应激和线粒体功能障碍通常是药物、毒物和创伤诱导的细胞死亡的中介。不幸的是，目前还没有真正有效的治疗方法来促进细胞和器官的修复/再生，以及损伤后器官功能的恢复。细胞通过线粒体的生物发生来取代陈旧和功能失调的线粒体。PGC-11通常被认为是脂肪组织、心脏和肝脏线粒体生物发生的主要调节因子，我们已经证明PGC-11介导了肾近端小管细胞(RPTC)的线粒体生物发生。此外，我们最近发现，PGC-11的过度表达导致RPTC中线粒体的生物发生，氧化损伤后增加线粒体的生物发生可以加速线粒体和细胞功能的恢复。这些令人兴奋的结果支持了损伤后线粒体生物发生可能在刺激细胞和器官修复/再生方面有效的假说。我们发现5-羟色胺2型受体(5-HT2)激动剂1-(2，5-二甲氧基-4-碘苯基)-2-氨基丙烷(DOI)能产生线粒体生物发生。RT-PCR分析RPTC中5-HT2受体亚型5-HT2a、5-HT2B和5-HT2C在人、兔、大鼠和小鼠中的表达。这些结果表明，在多种物种的RPTC中都发现了5-HT2受体，5-HT2受体的激活导致了线粒体的生物发生。最后，与单独使用氧化损伤相比，氧化损伤后用DOI处理RPTC加速了线粒体和细胞功能的恢复。此外，体内的初步研究表明，DOI在小鼠肾脏中产生线粒体生物生成[并加速I/R后肾功能的恢复]。这些研究支持我们的总体假设，即特定的5-HT2受体介导了线粒体的生物发生，并加速了急性肾损伤(AKI)后肾功能的恢复。以下特定目标将验证这一假说：1)特定目标1：确定负责RPTC线粒体生物发生的特定5-HT2受体亚型，2)特定目标2：阐明RPTC中5-HT2受体激活与线粒体生物发生耦合的信号转导途径，以及3)特定目标3：确定特定5-HT2受体激动剂对在体线粒体生物发生和小鼠肾I/R模型肾功能恢复的疗效。这些研究将探讨一个新的靶点，线粒体生物发生，以及一个新的线粒体生物发生途径，5-HT2受体，在急性器官损伤的治疗中，特别是AKI，使用细胞和体内模型。我们将结合分子生物学、生化和药理学方法来实现上述目标。最终，这些研究可能导致新的治疗方法，以提高细胞和器官的存活率和功能，在许多病理情况下。