The 5-hydroxytryptamine receptor 1F stimulates mitochondrial biogenesis and angiogenesis in endothelial cells.

A hallmark of acute kidney injury (AKI) is vascular rarefication and mitochondrial dysfunction. Promoting vascular recovery following AKI could facilitate kidney repair as the vasculature is responsible for oxygen and nutrient delivery to extravascular tissues. Little is known about mitochondrial biogenesis (MB) in endothelial cells, and the role of 5-HT receptor signaling in MB has only been studied in epithelial cells. Our laboratory has shown that stimulating MB through the 5-HT receptor promotes recovery from AKI and that 5-HT receptor knockout mice have decreased MB and poor renal recovery. We hypothesized that the 5-HT receptor plays a role in vascular homeostasis and mediates MB in renal endothelial cells. 5-HT receptor knockout mice had decreased renal vascular content, as evidenced by decreased CD31 endothelial cells and αSMA vessels. Human glomerular endothelial cells (HEC) and mouse glomerular endothelial cells (MEC) expressed the 5-HT receptor. Treatment of HEC and MEC with 5-HT receptor agonists LY344864 or lasmiditan (0-500 nM) induced MB as evidenced by maximal mitochondrial respiration, a marker of MB. HEC and MEC treated with lasmiditan or LY344864 also had increased nuclear- and mitochondrial-encoded proteins (PGC1α, COX-1, and VDAC), and mitochondrial number, confirming MB. Treatment of HEC with LY344864 or lasmiditan enhanced endothelial branching morphogenesis and migration, indicating a role for 5-HT receptor stimulation in angiogenic pathways. We propose that stimulation of 5-HT receptor is involved in MB in endothelial cells and that treatment with 5-HT receptor agonists could restore stimulate repair and recovery following kidney injury.