Lasmiditan promotes recovery from acute kidney injury through induction of mitochondrial biogenesis

Acute kidney injury (AKI) involves rapid loss of renal function and occurs in 8-16% of hospitalized patients. AKI can be induced by drugs, sepsis, and ischemia-reperfusion (I/R). Hallmarks of AKI include mitochondrial and microvasculature dysfunction as well as renal tubular injury. There is currently no available therapeutic for AKI. Previously, our group identified that serotonin (5-HT)_1F receptor agonism with lasmiditan accelerated endothelial cell recovery and induced mitochondrial biogenesis (MB) in vitro. We hypothesized that lasmiditan, a Federal Drug Administration-approved drug, would induce MB and improve microvascular and renal function in a mouse model of AKI. Male mice were subjected to renal I/R and treated with lasmiditan (0.3 mg/kg) or vehicle beginning 24 h after injury and then daily until euthanasia at 6 or 12 days. Serum creatinine was measured to estimate glomerular filtration rate. The renal cortex was assessed for mitochondrial density, vascular permeability and integrity, tubular damage, and interstitial fibrosis. Lasmiditan increased mitochondrial number (1.4-fold) in renal cortices. At 6 days, serum creatinine decreased 41% in the I/R group and 72% with lasmiditan. At 6 or 12 days, kidney injury molecule-1 increased in the I/R group and decreased 50% with lasmiditan. At 12 days, interstitial fibrosis decreased with lasmiditan by 50% and collagen type 1 by 38%. Evan's blue dye leakage increased 2.5-fold in the I/R group and was restored with lasmiditan. The tight junction proteins zonula occludens-1, claudin-2, and claudin-5 decreased in the I/R group and recovered with lasmiditan. At 6 or 12 days, peroxisome proliferator-activated receptor-c coactivator-1a and electron transport chain complexes increased only with lasmiditan. In conclusion, lasmiditan treatment beginning AKI induces MB, attenuated vascular and tubular injury, decreased interstitial fibrosis, and lowered serum creatinine. Given that lasmiditan is a Federal Drug Administration-approved drug, these preclinical data support repurposing lasmiditan as a therapeutic for AKI.