# Cellular cholesterol and podocyte function in diabetic kidney disease

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $410,359

## Abstract

ABSTRACT
Podocyte injury is a key feature of DKD and renal accumulation of lipid correlates with the development of
glomerulosclerosis. Decreased expression of ATP-binding cassette transporter 1 (ABCA1) occurs in glomerular
transcripts from patients DKD and is associated with the presence of podocyte lipid droplets in kidney biopsies.
Fibroblasts from patients with Tangier disease carrying ABCA1 loss of function mutations are characterized by
cardiolipin accumulation, a mitochondrial specific phospholipid. While increases in hepatic cholesterol and
cardiolipin content are observed in association with mitochondrial dysfunction in patients with non-alcoholic
steatohepatitis (NASH), h yperglycemia induced excess mitochondrial superoxide production has been
considered the primary driver of mitochondrial dysfunction in DKD. These observations led us to hypothesize
that ABCA1 deficiency renders podocytes susceptible to DKD-mediated injury via cardiolipin dependent
mitochondrial dysfunction.
Our preliminary data suggest that ABCA1 deficiency leads to changes in the mitochondrial membrane lipid
composition and CL accumulation in association with mitochondrial dysfunction and oxidative stress in vitro
rendering podocyte susceptible to injury. In vivo, we demonstrate that podocyte specific Abca1 deficiency
(pABCA1) is associated with accumulation of esterified cholesterol in kidney cortex but is not sufficient to cause
proteinuria. However, Abca1 deficient podocytes cultured in diabetic milieu are more susceptible to DKD-related
injury and pABCA1 diabetic mice have worsened DKD progression and accumulation of docosahexaenoic acid
(DHA)-rich cardiolipin, a cardiolipin species especially susceptible to reactive oxygen species (ROS). The
phenotype of these mice can be partially rescued by inhibition of cardiolipin peroxidation with Elamipretide, an
inhibitor of CL peroxidation.
We propose three specific aims to test several hypotheses. In specific aim 1, we will determine if ABCA1
deficiency and hyperglycemia contribute differently to mitochondrial (dys)function. In specific aim 2, we will
investigate the effect of ABCA1 deficiency on the lipid composition and fluidity of mitochondrial membranes and
in specific aim 3, we will determine if inhibition of cardiolipin peroxidation can rescue ABCA1 dependent
mitochondrial dysfunction.
This innovative study is aimed at deciphering the role of ABCA1-mediated lipid compartmentalization and CL
accumulation in mitochondrial dysfunction and podocyte injury. If successful, this study will have high impact
as it elucidates a new pathway important in podocyte injury and may lead to the identification of new drug targets
for the treatment of patients with DKD.

## Key facts

- **NIH application ID:** 10189567
- **Project number:** 5R01DK104753-07
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** ALESSIA FORNONI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,359
- **Award type:** 5
- **Project period:** 2015-03-20 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189567

## Citation

> US National Institutes of Health, RePORTER application 10189567, Cellular cholesterol and podocyte function in diabetic kidney disease (5R01DK104753-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10189567. Licensed CC0.

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