5-hydroxytryptamine 1F receptor loss reduces renal vasculature and prevents lasmiditan-induced recovery following moderate-severe acute kidney injury in mice.

Abstract

Kidney disease (KD) has emerged as a major global health crisis and leading cause of morbidity and mortality worldwide, impacting over 850 million individuals. Pathophysiological hallmarks of KD encompass renal tubular cell injury/necrosis, tubulointerstitial fibrosis, vascular dysfunction/rarefaction, and mitochondrial dysfunction, all of which are implicated in disease initiation/progression. Unfortunately, there remains a general lack of effective FDA-approved therapeutics for the treatment of KD. Thus, the identification of novel and/or repurposed treatment strategies remains of dire importance. Previously, we identified the 5-hydroxytryptamine 1F receptor (HTR1F) as a modulator of renal mitochondrial homeostasis, and demonstrated that mice lacking this receptor exhibit hindered renal recovery following mild ischemia/reperfusion-induced acute kidney injury (I/R-AKI). Additionally, we reported that treatment with the HTR1F agonist lasmiditan, an FDA approved therapeutic for acute migraines, expedites renal recovery following I/R-AKI in mice. Here, we show that lasmiditan treatment following moderate-severe I/R-AKI ameliorates acute tubular injury, mitochondrial dysfunction, tubulointerstitial fibrosis, and vascular rarefaction in the renal cortex of mice, which likely contributes to the enhanced recovery observed. Importantly, we also confirm that this lasmiditan-induced renal recovery is contingent on HTR1F expression. Furthermore, mice lacking the HTR1F exhibit decreased innate renal cortical vasculature, exacerbated rarefaction, and markedly increased mortality rates following moderate-severe I/R-AKI. These findings not only underscore the importance of HTR1F expression and agonism in renal repair and recovery, but also further highlight the repurposing potential of lasmiditan for the treatment of AKI and/or KD onset/progression.