# Ceramides as Novel Mediators of Tubular Metabolic Dysfunction Driving Kidney Injury

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $32,386

## Abstract

PROJECT SUMMARY/ABSTRACT. Acute kidney injury (AKI) is a prevalent condition which elicits an enormous
burden on patient mortality and healthcare spending. A significant unmet need exists to elucidate kidney-specific
insults driving the onset and progression of kidney injury in order to develop novel therapeutic strategies capable
of directly targeting renal pathology. Compelling evidence has suggested that altered metabolism within the
kidney proximal tubule is implicated in AKI. The work proposed in this fellowship application will critically evaluate
the role of a class of lipotoxic lipid species, termed ceramides, as drivers of mitochondrial dysfunction, oxidative
stress, and lipid accumulation characteristic of multiple kidney pathologies. Human correlational data suggest
that altered tubular ceramide metabolism correlates with clinical kidney disease endpoints, such as kidney
fibrosis and estimated glomerular filtration rate. Previous reports indicate that renal ceramides are elevated in
pre-clinical models following kidney injury or in the setting of chronic disease, and preliminary data presented
herein demonstrate that whole-body depletion of ceramides successfully prevents acute kidney injury and
histopathology following renal ischemia reperfusion or obstructive injury. This application intends to address the
remaining gap in knowledge regarding whether local kidney ceramides play a role in disease mechanisms and
in which cell types. Specifically, the proposed project will determine if ceramides are candidate mediators of
metabolic dysfunction in tubular epithelial cells. In Aim One, we will probe for protection from kidney injury
incurred in novel mouse lines with genetic depletion of ceramides in the kidney tubular epithelium. Furthermore,
animals with genetic gain-of-ceramide within kidney tubules will be assessed for development of kidney
dysfunction and histopathology. Studies proposed in Aim Two will employ in vitro and ex vivo methods to
characterize novel mechanisms of ceramides driving impairment of mitochondrial bioenergetics and lipid
accumulation in kidney tubules and primary cells. Preliminary findings demonstrate that accumulation of
ceramides impairs mitochondrial respiration and ATP production in cultured immortalized proximal tubular
epithelial cells. This work will be the first investigation to directly assess if tubule-derived ceramides are
implicated in the metabolic perturbations preceding tubular injury and histopathology and will provide valuable
insight into the therapeutic potential of ceramide-lowering interventions for dominant causes of acute kidney
injury. Furthermore, completion of the proposed studies will greatly enrich the applicant’s pre-doctoral training,
mastery of technical skills (e.g., implementation and evaluation of kidney injury and disease models, evaluation
of mitochondrial metabolism and substrate utilization, and mass spectrometry-based analysis of ceramide
levels), and development as a youn...

## Key facts

- **NIH application ID:** 10917083
- **Project number:** 5F31DK134088-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** REBEKAH JOY NICHOLSON
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $32,386
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-04-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917083

## Citation

> US National Institutes of Health, RePORTER application 10917083, Ceramides as Novel Mediators of Tubular Metabolic Dysfunction Driving Kidney Injury (5F31DK134088-02). Retrieved via AI Analytics 2026-07-16 from https://api.ai-analytics.org/grant/nih/10917083. Licensed CC0.

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