Kidney Week

Abstract: SA-PO136

The FDA-Approved Drug Lasmiditan Augments Primary Mouse Renal Peritubular Endothelial Cell Wound Healing and Angiogenic Capacity

Session Information

• AKI: Metabolism and Cell Death
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Thompson, Austin D., The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Austin D. Thompson, MS

• Janda, Jaroslav, The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Jaroslav Janda, PhD

• Schnellmann, Rick G., The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Rick G. Schnellmann, PhD

Background

Acute kidney injury (AKI) remains a significant public health concern with no FDA-approved treatments. AKI often involves mitochondrial dysfunction, tubular injury/necrosis, and microvascular damage/rarefaction, all of which exacerbate renal injury and increase the risk of developing chronic kidney disease.
Pharmacological stimulation of mitochondrial biogenesis (MB) has been shown to enhance mitochondrial function and renal vascular recovery post-AKI; however, its role in relation to renal peritubular endothelial cell repair mechanisms remains unknown. To address this gap in knowledge, we conducted wound healing and tube formation assays using primary mouse renal peritubular endothelial cells (MRPEC) exposed to tumor necrosis factor-alpha (TNFα) in the presence/absence of lasmiditan, a HTR1F agonist known to induce MB in the renal cortices of mice.

Methods

Primary MRPEC were isolated as previously described by Thompson et al. (2023). For wound healing assays, MRPEC were seeded onto fibronectin-coated Ibidi wound healing dishes (7x10⁴ cells/well) and incubated overnight in microvascular media (EGM-MV2). MRPEC were then treated with TNFα [100ng/mL] or vehicle [saline+0.1%DMSO], with/without lasmiditan [100nM], and chamber inserts were removed. Dishes were imaged 24h post-treatment. For tube formation assays, MRPEC were treated for 24h, as described above, and seeded onto growth factor reduced Matrigel-coated Ibidi 3D-angiogenesis µ-Slides (1.5x10⁴ cells/well). Cells were incubated overnight in EGM-MV2 and imaged the following day. All images were analyzed via Ibidi FastTrackAI software.

Results

Lasmiditan-treated MRPEC exhibited 1.15- and 1.10-fold increases in wound closure and 2.40- and 7.21-fold increases in tubular branch formation, compared to vehicle- and TNFα-treated controls, respectively. Cells treated with both TNFα and lasmiditan exhibited 1.22- and 1.16-fold increases in wound closure compared to vehicle- and TNFα-treated controls, and a 2.98-fold increase in tubular branch formation compared to TNFα-treated cells.

Conclusion

Together, these data reveal that lasmiditan augments MRPEC wound healing and angiogenic capacity, independently and in response to TNFα-induced cellular injury, suggesting a potential role for lasmiditan treatment in promoting vascular recovery post-kidney injury.

Funding

• Other NIH Support