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: 8597388
• 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/8597388
• 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. PUBLIC HEALTH RELEVANCE: Acute Kidney Injury remains an enormous public health concern as no truly effective therapies have proven to be useful after renal injury. Mitochondrial biogenesis, the process of replacing dysfunctional mitochondria presents a novel avenue for stimulating cell and organ repair/regeneration after renal injury, promoting the return of renal function. Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic conditions.

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理治疗方法。氧化应激引起的细胞损伤和死亡发生在缺血/再灌注期间（I/R），导致心脏，脑，肝脏和肾脏等不同器官的失败。 I/R导致线粒体功能障碍，这是通过增强氧化剂产生并减少ATP合成的细胞损伤和死亡的主要机制。此外，氧化应激和线粒体功能障碍通常是药物，毒物和创伤引起的细胞死亡的介体。不幸的是，没有真正有效的疗法可以促进细胞和器官修复/再生以及受伤后器官功能的恢复。 细胞通过线粒体生物发生取代旧的和功能障碍的线粒体。过氧化物酶体增殖物激活的受体γ共激活剂11（PGC-111）通常被认为是脂肪组织，心脏和肝脏中线粒体生物发生的主要调节剂，我们已经证明PGC-111表明PGC-11介导了肾脏额额核细胞中的线粒体生物发生。此外，我们最近表明，PGC-11的过度表达会导致RPTC中的线粒体生物发生，并且在氧化剂损伤后增加线粒体生物发生加速了线粒体和细胞功能的恢复。这些令人兴奋的结果支持以下假设：损伤后线粒体生物发生可能有效地刺激细胞和器官修复/再生。 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），产生了线粒体生物发生。从RPTC分离的mRNA的RT-PCR分析证实了人类，兔子，大鼠和小鼠的5-HT2受体亚型5-HT2A，5-HT2B和5-HT2C的表达。这些结果表明，在多种物种的RPTC中发现了5-HT2受体，而5-HT2受体的激活会导致线粒体生物发生。最后，与单独的氧化剂损伤相比，氧化剂损伤后用DOI处理RPTC可以加速线粒体和细胞功能的回归。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发生[并加速了I/R。]肾功能的恢复。以下具体目的将检验以下假设：1）具体目标1：确定负责线粒体生物发生的特定5-HT2受体亚型，RPTC中的线粒体生物发生，2）特定目标2：阐明信号传输途径，使5-HT2受体激活在RPTC中的受体特殊性3）coption 5-HT2受体激活的受体特定于3：3）：线粒体生物发生在体内和肾脏I/R小鼠模型中肾功能的恢复。 这些研究将检查一个新靶标，线粒体生物发生以及使用细胞和体内模型治疗急性器官损伤（特别是AKI）的线粒体生物发生的新途径5-HT2受体。我们将结合分子生物学，生化和药理学方法来完成上述目的。最终，这些研究可能导致新的治疗方法，以增加细胞和器官的生存和在许多病理状况中的功能。 公共卫生相关性： 急性肾脏损伤仍然是一个巨大的公共卫生问题，因为在肾脏受伤后没有真正有效的疗法有用。线粒体生物发生，替换功能障碍线粒体的过程提出了一种刺激细胞和器官修复/再生肾脏损伤后的新途径，从而促进了肾功能的回归。最终，这些研究可能导致新的治疗方法，以增加细胞和器官的生存和在许多病理状况下的功能。