# The Role of Kidney-derived APOM in S1P-mediated glomerular injury

> **NIH NIH F31** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $26,343

## Abstract

Abstract
Chronic kidney disease is one of the most prevalent diseases around the world, affecting over 35 million people
in the United States alone. Of these, roughly 15% of cases are attributed to glomerular diseases such as Alport
Syndrome (AS), which progresses to end stage renal disease in 90% of patients by the age of 40. Despite
knowing the genetic underpinnings of AS, the downstream mechanisms are not fully understood, making it
difficult to create targeted therapies for patients. Work from us and others have implicated the dysregulation of
sphingolipid metabolism and signaling in the progression of glomerular disease via injury to the podocyte, a
specialized glomerular cell which is crucial for renal filtration. The involvement of sphingosine-1-phosphate
(S1P), a highly bioactive sphingolipid, is implicated in glomerular pathology. We have shown that the expression
of Apolipoprotein M (ApoM), the physiologic carrier of S1P, is inversely correlated with albuminuria in CKD
patients. Similarly, our preliminary studies show an association between ApoM deficiency and podocyte/renal
injury in vitro and in vivo.
Aim 1 will investigate if ApoM deficiency exacerbates S1P-mediated podocyte injury. Our preliminary data
show that Col4a3-/- mice, a model of AS, have significantly decreased APOM in the renal cortex, mirroring the
phenotype in human patients. Furthermore, they also show S1P accumulation in kidney cortex in association
with glomerular apoptosis, while treatment with recombinant APOM restores these phenotypes and improves
renal function. This aim leverages lipidomic analyses, advanced microscopy modalities, and renal phenotype
evaluation to determine the role of S1P in mediating podocyte injury. This aim will use various in vitro and in vivo
analyses in lentiviral siAPOM cells and renal APOM deficient kAPOMASO-/- mice to establish the role of kidney-
derived APOM in modulating S1P content and downstream podocyte injury.
Aim 2 will Determine if renal ApoM replenishment is sufficient to rescue from S1P-mediated renal
injury associated with AS. Our preliminary data show that treatment of Col4a3-/- mice with rhApoM in vivo
prevents the progression of kidney injury. Importantly, Col4a3-/- mice have decreased ApoM expression in the
kidney cortex, while treatment with rhApoM restores renal ApoM expression in vivo. We hypothesize that
kidney derived ApoM plays a role in preventing S1P accumulation and consequent glomerular injury in AS.
This aim seeks to show that restoring the expression of ApoM in Col4a3-/- podocytes will be sufficient to
protect from S1P-mediated injury and restore S1P levels in vitro. We also expect that restoration of renal ApoM
expression with AAV gene delivery will prevent progression of proteinuria in Col4a3-/- mice.

## Key facts

- **NIH application ID:** 10995741
- **Project number:** 1F31DK141124-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Antonio Miguel Fontanella
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $26,343
- **Award type:** 1
- **Project period:** 2024-12-01 → 2025-04-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995741

## Citation

> US National Institutes of Health, RePORTER application 10995741, The Role of Kidney-derived APOM in S1P-mediated glomerular injury (1F31DK141124-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10995741. Licensed CC0.

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