# 5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury

> **NIH VA I01** · SOUTHERN ARIZONA VA HEALTH CARE SYSTEM · 2022 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
 Acute Kidney Injury (AKI) is a devastating disease with high mortality and no treatments. Common causes
of AKI in the VETERAN population include sepsis, trauma, drug/toxicant exposure, and ischemia/reperfusion
(IR). The long-term goal of our laboratory is to uncover novel mechanisms of AKI and develop therapeutics to
promote recovery. Following AKI, a marked reduction in renal microvasculature is observed and results in the
loss of oxygen and nutrients to extravascular tissue needed for tissue repair. In addition, there is persistent
mitochondrial dysfunction following AKI. Pathways mediating vascular repair and mitochondrial biogenesis (MB)
are under-studied. We previously confirmed the presence of the 5-HT1F receptor in renal proximal tubular cells
(RPTC) and identified the pathways of 5-HT1F receptor-mediated MB. The 5-HT1F receptor knockout mouse has
altered renal mitochondrial homeostasis and impaired renal recovery following IR-induced AKI, while the 5-HT1F
receptor agonist lasmiditan stimulated MB and improved renal recovery.
 Unlike RPTC, endothelial cells (EC) primarily derive their energy through aerobic glycolysis with limited
mitochondria and oxidative phosphorylation. Stimulation of MB via the 5-HT1F receptor in EC may promote
vascular recovery following AKI. Our preliminary data reveal that (i) primary cultures of mouse renal peritubular
endothelial cells (MRPEC) express the 5-HT1F receptor, (ii) treatment of MRPEC with lasmiditan induces MB and
increases mitochondrial function, (iii) lasmiditan stimulates MRPEC branching and wound closure, (iv) lasmiditan
stimulates MB in EC in mice, (v) lasmiditan decreases vascular leakage and improves renal recovery, (vi) mice
lacking the 5-HT1F receptor have decreased renal vasculature, and (vii) lasmiditan does not induce renal MB in
mice lacking the 5-HT1F receptor. Thus, our previous and current work suggest a role for the 5-HT1F receptor in
stimulating MB and angiogenesis in EC followingAKI.
 We hypothesize that lasmiditan, a recently FDA-approved drug, induced activation of the 5-HT1F receptor
in renal vascular endothelium promotes MB and angiogenesis, resulting in decreased vascular rarefication,
increased vascular function, and promotion of renal recovery from AKI.
 We will test this hypothesis with the following specific aims. Aim 1 will determine the 5-HT1F receptor
signaling pathway(s) responsible for MB and angiogenesis in response to the 5-HT1F receptor agonist lasmiditan
in MRPEC. Aim 2 will determine the effects of normoxia, oxidant exposure, and pro-inflammatory conditions on
MB and angiogenesis, and elucidate the efficacy and mechanism of lasmiditan in restoring mitochondrial function
and angiogenesis in MRPEC. Aim 3 will determine the role of 5-HT1F receptor expression in EC and RPTC in
vascular and renal recovery in the presence and absence of lasmiditan following IR injury AKI.

## Key facts

- **NIH application ID:** 10368276
- **Project number:** 2I01BX000851-09A1
- **Recipient organization:** SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
- **Principal Investigator:** Rick G Schnellmann
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2010-10-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368276

## Citation

> US National Institutes of Health, RePORTER application 10368276, 5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury (2I01BX000851-09A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10368276. Licensed CC0.

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