Stimulation of 5‐HT 1F Receptor Increases Vascular Recovery Following Ischemia/Reperfusion‐Induced AKI

Acute kidney injury (AKI) is a disease with no treatment. After AKI, there is a marked reduction in renal vasculature. Thus, promoting vascular recovery following AKI could facilitate renal repair as the vasculature is responsible for carrying oxygen and nutrients to extravascular tissues. Our laboratory has shown that stimulating mitochondrial biogenesis (MB) through the 5‐HT 1F receptor stimulates recovery from AKI and 5‐HT 1F receptor knockout mice have decreased MB and poor renal recovery. Importantly, we have shown that stimulation of the 5‐HT 1F receptor with LY344864 or lasmiditan induces MB, branching morphogenesis, and migration in human renal glomerular endothelial cells (EC) in vitro . We hypothesize that the 5‐HT 1F receptor plays a role in renal vascular recovery following AKI. 5‐HT 1F receptor KO mice have decreased CD31+ and aSMA+ ECs in the kidney, suggesting that the 5‐HT 1F receptor plays a role in renal vascular homeostasis. To assess the role of the 5‐HT 1F receptor in renal vascular injury, WT and 5‐HT 1F receptor KO mice were subjected to IR‐induced AKI. 5‐HT 1F receptor KO mice exhibited increased renal Evans blue dye (EBD) extravasation in comparison to I/R injured WT mice 24h following injury, suggesting increased vascular injury. To assess the role of 5‐HT 1F receptor in renal vascular recovery following IR‐induced AKI, WT mice were treated with LY344864 (2 mg/kg) beginning 24h after I/R‐induced AKI. LY344864 decreased renal EBD extravasation 144h following injury compared to vehicle treated AKI mice, suggesting that stimulation of 5‐HT 1F receptor increases vascular recovery. We also assessed whether or not lasmiditan, a more specific and potent 5‐HT 1F receptor agonist which has recently been FDA approved, would induce MB in vivo . Mice were treated with lasmiditan (0.3 mg/kg) for 24h had increased protein levels of PGC1a and TFAM, both of which are regulators of MB and markers of MB. Taken together, these data indicate a role for 5‐HT 1F receptor signaling in renal vascular injury and repair following I/R‐induced AKI. We propose that inducing MB in ECs after AKI restores vascular function and stimulates renal repair and recovery, and that repurposing lasmiditan as a treatment option for AKI may prove useful. Support or Funding Information This work was supported by F32 DK120222‐01A1 to TVD (National Institute of Health) and 1BX000851 (Department of Veterans Affairs) to RGS.