Kidney Week

Abstract: SA-PO0146

Loss of HTR1F Expression Increases Mortality and Prevents Lasmiditan-Induced Kidney Recovery After Moderate to Severe AKI in Mice

Session Information

• AKI: Mechanisms - 3
  November 08, 2025 | 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

• Mcalister, Kai W., The University of Arizona College of Pharmacy, Tucson, Arizona, United States

Kai W. Mcalister, B.S.

• 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

Group or Team Name

• Schnellmann Lab.

Background

Kidney disease (KD) ranks among the leading causes of global morbidity and mortality. Moreover, acute kidney injury (AKI) remains a significant health concern lacking FDA-approved treatments. AKI often results in tubular injury/necrosis, mitochondrial dysfunction, and fibrosis, all of which increase the risk of AKI-recurrence and KD onset/progression.
Pharmacological induction of mitochondrial biogenesis (MB) is known to confer renoprotective effects post-AKI and in various KDs. Lasmiditan (Las), an FDA-approved HTR1F agonist, was previously shown to induce MB and expediate renal recovery after ischemia/reperfusion induced-AKI (I/R-AKI) in mice. Here, we confirm Las-induced renal recovery is contingent on HTR1F expression, and mice lacking HTR1F exhibit increased mortality after moderate-severe I/R-AKI.

Methods

HTR1F^Fl/Fl floxed mice were generated by 5’/3’loxP insertions, and EIIa-Cre was used to generate HTR1F whole-body knockout mice (EIIa-Cre/HTR1F^Fl/Fl); all mice were confirmed by PCR. Male HTR1F^Fl/Fl, EIIa-Cre/HTR1F^Fl/Fl, and C57BL/6NCrl (WT-Purchased) mice (8-10 weeks-old) were subjected to moderate-severe bilateral IR-AKI. For each genotype, mice were randomly assigned to groups: 1)Sham, 2)I/R24h, 3)I/R7d+vehicle(Veh), 4)I/R7d+Las[0.3mg/kg], 5)I/R14d+Veh, or 6)I/R14d+Las. Mice in groups 2–6 had an average serum creatinine (SCr) of 1.5±0.1mg/dl and met a 1.3-1.8mg/dl SCr experimental inclusion criteria 24h post-injury. Mice in groups 3-6 received daily dosing (i.p.), starting 24h post-injury, until above endpoints were achieved. Mice were then euthanized and blood and kidneys were collected for analyses.

Results

WT-Purchased and HTR1F^Fl/Fl mice displayed no difference in mortality. Conversely, loss of HTR1F nearly doubled the risk of mortality after moderate-severe I/R-AKI, reducing the probability of survival in EIIa-Cre/HTR1F^Fl/Fl mice to 52%, irrespective of treatment. Both WT-Purchased and HTR1F^Fl/Fl Las-treated mice exhibited a ~20% reduction in SCr 7d post I/R-AKI compared to vehicle-treated controls, an effect not observed in EIIa-Cre/HTR1F^Fl/Fl mice.

Conclusion

These data underscore the importance of HTR1F expression and agonism in renal repair and recovery, and further highlight the repurposing potential of lasmiditan for the treatment of AKI and/or KD onset/progression.

Funding

• Other NIH Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20252cbtpg76