5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury

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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.