Stimulation of Mitochondrial Biogenesis with 5-HT Receptor Agonists

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DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a rapid-onset disease with significant morbidity and mortality that affects up to 5% of long-term hospital patients. Most cases of AKI result from renal ischemia/reperfusion (I/R) or acute drug or toxicant exposure. The development of therapeutic strategies to treat AKI in humans has been largely unsuccessful and the mortality resulting from AKI has remained unchanged for several decades. Therefore, the development of more successful therapies necessitates the examination of novel targets. It has been demonstrated that renal proximal tubule cells exposed to acute oxidant injury, such as that found in acute I/R or toxicant exposure, exhibit serious mitochondrial dysfunction. It has been further demonstrated that the recovery of mitochondrial function in these cells is temporally related to recovery of cellular function, and that the recovery of mitochondrial function is temporally related to the expression of peroxisome-proliferator- receptor-3-coactivator-11 (PGC-11), the "master regulator" of mitochondrial biogenesis. Our lab has recently demonstrated that 5-HT2 receptor agonists stimulate mitochondrial biogenesis in vitro by increasing the expression of PGC-11. We first seek to examine the signaling pathway between 5-HT2 receptor activation and PGC-11 expression and to verify our in vitro data in an animal model. We then intend to test our hypothesis that 5-HT2 receptor agonists will induce mitochondrial biogenesis and promote recovery of kidney function after in an animal model of acute I/R injury. Specific Aims: 1) Elucidate the 5-HT2 signaling pathway of mitochondrial biogenesis. 2) Determine the 5-HT2 signaling pathway of renal mitochondrial biogenesis in mice. 3) Determine the effect of 5-HT2 agonists on the recovery of renal function following I/R injury. Methods: The first aim will be accomplished by using pharmacological inhibitors to signaling pathway enzymes proposed to be involved in the stimulation of mitochondrial biogenesis by 5-HT2 receptor agonists. The second aim will be accomplished by "knocking down" components of the elucidated signaling pathway in mice using siRNA and measuring mitochondrial biogenesis as a result of 5-HT2 receptor agonist treatment. The third aim will be performed by subjecting mice to a model of I/R acute kidney injury and treating them with 5-HT2 receptor agonists. These mice will be monitored for improvements in kidney function in the presence and absence of these agonists. Goal: To further understand the role and signaling pathway of 5-HT2 receptor agonists in stimulating mitochondrial biogenesis and to probe their usefulness as novel therapeutics to treat acute kidney injury. Relevance to agency: Toxicant exposure is a significant culprit in the pathogenesis of acute kidney injury; these toxicants may be intentionally administered, such as nephrotoxic chemotherapeutics, or unintentionally introduced, such as in the case of environmental heavy metal exposure. This work seeks to examine the usefulness of 5-HT2 receptor agonists in the treatment of this acute disease state.