5-HT1F receptor mediated mitochondrial biogenesis in Vascular Recovery Following Acute Kidney injury

University Of Arizona, Tucson AZ

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Acute Kidney Injury (AKI) is a devastating disease with high mortality and no treatments. Following an AKI episode, a marked reduction in renal microvasculature is observed. The microvasculature is needed to carry oxygen and nutrients to extravascular tissue during tissue repair. In the context of AKI, little attention has focused on pathways mediating vascular repair. In addition to reduced renal microvasculature, AKI results in a persistent reduction in mitochondrial function and cellular energetics, while stimulation of MB promotes renal recovery from AKI. Our laboratory has identified the presence of the 5-HT1F receptor in the kidney and elucidated the signaling pathway in which a 5-HT1F receptor agonist (LY344864) induces renal MB and stimulates recovery of renal function following AKI. In addition, we found that loss of 5-HT1F receptor dependent MB is likely the mechanism by which mitochondrial homeostasis and MB are diminished following AKI, and this suppression prevents proper recovery from AKI. While previous studies have only focused on the role of 5-HT1F receptor mediated MB in renal proximal tubule cells, both renal proximal tubule cells and endothelial cells are involved in the injury and recovery phases of AKI. Thus, understanding how the 5-HT1F receptor mediates MB in endothelial cells to promote recovery from AKI is important. We recently found that that human and mouse renal endothelial cells express the 5-HT1F receptor, and treatment of these cells with 5-HT1F receptor agonists (LY344864, lasmiditan) induce MB as evidenced by increased expression of both nuclear- and mitochondrial-encoded proteins and increased oxygen consumption. In addition, we found that mice lacking the 5-HT1F receptor have decreased renal vasculature. Thus, we hypothesize that LY344864/lasmiditan activation of 5-HT1F receptors in the vascular endothelium promotes MB resulting in decreased vascular rarefication, increased vascular function, and promotion of renal recovery from AKI. We will test this hypothesis in the following specific aims. Aim 1 will determine the 5-HT1F receptor signaling pathway(s) responsible for MB under normoxic and hypoxic/reoxygenation conditions in response to 5-HT1F receptor agonists lasmiditan/LY344864 in human and mouse renal endothelial cells. Aim 2 will elucidate the role of the 5-HT1F receptor in renal vascular injury and recovery following ischemia/reperfusion-induced AKI and the efficacy of lasmiditan/LY344864 in promoting renal vascular recovery following injury in mice. Aim 3 will determine the role of 5-HT1F receptor expression in endothelial cells and proximal tubular cells following AKI. Cre-lox technology will be used to generate mouse models specifically lacking 5-HT1F receptor in each of the aforementioned cell types.