5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury

PROJECT SUMMARY/ABSTRACT Acute Kidney Injury (AKI) is a devastating disease with high mortality and no treatments. Common causes of AKI in the VETERAN population include sepsis, trauma, drug/toxicant exposure, and ischemia/reperfusion (IR). The long-term goal of our laboratory is to uncover novel mechanisms of AKI and develop therapeutics to promote recovery. Following AKI, a marked reduction in renal microvasculature is observed and results in the loss of oxygen and nutrients to extravascular tissue needed for tissue repair. In addition, there is persistent mitochondrial dysfunction following AKI. Pathways mediating vascular repair and mitochondrial biogenesis (MB) are under-studied. We previously confirmed the presence of the 5-HT1F receptor in renal proximal tubular cells (RPTC) and identified the pathways of 5-HT1F receptor-mediated MB. The 5-HT1F receptor knockout mouse has altered renal mitochondrial homeostasis and impaired renal recovery following IR-induced AKI, while the 5-HT1F receptor agonist lasmiditan stimulated MB and improved renal recovery. Unlike RPTC, endothelial cells (EC) primarily derive their energy through aerobic glycolysis with limited mitochondria and oxidative phosphorylation. Stimulation of MB via the 5-HT1F receptor in EC may promote vascular recovery following AKI. Our preliminary data reveal that (i) primary cultures of mouse renal peritubular endothelial cells (MRPEC) express the 5-HT1F receptor, (ii) treatment of MRPEC with lasmiditan induces MB and increases mitochondrial function, (iii) lasmiditan stimulates MRPEC branching and wound closure, (iv) lasmiditan stimulates MB in EC in mice, (v) lasmiditan decreases vascular leakage and improves renal recovery, (vi) mice lacking the 5-HT1F receptor have decreased renal vasculature, and (vii) lasmiditan does not induce renal MB in mice lacking the 5-HT1F receptor. Thus, our previous and current work suggest a role for the 5-HT1F receptor in stimulating MB and angiogenesis in EC followingAKI. We hypothesize that lasmiditan, a recently FDA-approved drug, induced activation of the 5-HT1F receptor in renal vascular endothelium promotes MB and angiogenesis, resulting in decreased vascular rarefication, increased vascular function, and promotion of renal recovery from AKI. We will test this hypothesis with the following specific aims. Aim 1 will determine the 5-HT1F receptor signaling pathway(s) responsible for MB and angiogenesis in response to the 5-HT1F receptor agonist lasmiditan in MRPEC. Aim 2 will determine the effects of normoxia, oxidant exposure, and pro-inflammatory conditions on MB and angiogenesis, and elucidate the efficacy and mechanism of lasmiditan in restoring mitochondrial function and angiogenesis in MRPEC. Aim 3 will determine the role of 5-HT1F receptor expression in EC and RPTC in vascular and renal recovery in the presence and absence of lasmiditan following IR injury AKI.