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Kidney Week

Abstract: PO0345

FDA-Approved Drug Lasmiditan Stimulates Mitochondrial Biogenesis and Promotes Recovery of Vasculature and Renal Function After Ischemia-Reperfusion Injury in Mice

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hurtado, Kevin A., The University of Arizona College of Pharmacy, Tucson, Arizona, United States
  • Janda, Jaroslav, The University of Arizona College of Pharmacy, Tucson, Arizona, United States
  • Schnellmann, Rick G., The University of Arizona College of Pharmacy, Tucson, Arizona, United States
Background

Acute kidney injury (AKI) is induced by multiple mechanisms (e.g. ischemia/reperfusion (I/R), drugs, sepsis) and results in tubular and vascular dysfunction. Mitochondrial dysfunction is a key mediator of injury and recent studies have shown that pharmacological-induced mitochondrial biogenesis (MB) can provide renal recovery. Activation of the 5-HT1F receptor has been demonstrated to induce MB in the mouse kidney and the absence of said receptor results in greater renal injury from I/R, demonstrating the importance of the 5-HT1F receptor in the kidney. The goal of this study was to test the efficacy of the potent, selective, and FDA-approved 5-HT1F receptor agonist lasmiditan in a mouse I/R-induced AKI model.

Methods

Male mice were subjected to I/R-induced AKI. After 24 h, serum creatinine was measured and I/R mice were divided into two groups and dosed with lasmiditan (0.3 mg/kg) or vehicle. Daily dosing was continued until euthanasia at 144 h. Electron microscopy was used to measure mitochondrial number. Serum creatinine was measured. Vascular leakage was determined using Evan’s blue dye and tight junction proteins. Mitochondrial proteins and KIM-1 were measured using immunoblot analysis.

Results

Treatment with lasmitidan increased renal cortex mitochondrial number by 33%. Serum creatinine levels were similar between the I/R+vehicle group and I/R+lasmiditan group at 24 h. At 144 h, serum creatinine markedly decreased by 72% and KIM-1 decreased by 50% in I/R+lasmiditan group compared to I/R+vehicle group, respectively. PGC-1α and electron transport chain complexes IV and V were restored in I/R+lasmiditan group. Vascular permeability increased 2.5-fold in the I/R+vehicle group and was restored to control levels in the I/R+lasmiditan group. The tight junction proteins occludin, ZO-1, and Claudin 5 decreased in the I/R+vehicle group and was restored to control levels in the I/R+lasmiditan group.

Conclusion

In this study we demonstrate that FDA approved lasmiditan restores mitochondrial function and renal and vascular function after I/R injury in mice. Lasmiditan could be repurposed for the treatment of AKI in humans.

Funding

  • Veterans Affairs Support