# Sphingolipids in Acute Kidney Injury and Disease Progression

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $490,020

## Abstract

The overall goal of the current proposal is to understand the mechanisms by which targeting the sphingolipid
pathway can prevent or attenuate progressive kidney fibrosis. ~20-40M people in the United States have kidney
diseases and new treatments are urgently needed. Targeting the sphingolipid pathway serves as an important
area for biological research that will undergird novel therapeutic interventions for the treatment of progressive
kidney fibrosis. Sphingosine 1-phosphate (S1P) is the naturally occurring ligand of the S1P receptors (S1PR)
and is present in both extracellular and intracellular compartments. The effects of extracellular S1P are mediated
through S1PR1-5, which are differentially expressed by a variety of cell types. Intracellular S1P is controlled by
manipulating S1P synthesis, degradation, or export. Intracellular S1P is a key signaling molecule that has
multifunctional roles, depending on its compartmentalization. Intracellular S1P is generated by phosphorylation
of sphingosine by two sphingosine kinases (Sphk1 and Sphk2). Sphk1 is localized to the cytoplasm and Sphk2
localized to the nucleus, mitochondria, and endoplasmic reticulum. We observed markedly attenuated renal
fibrosis in Sphk2-/- mice compared to Sphk1-/- or WT mice and in mice with tissue specific deletion of Sphk2 in
pericyte/perivascular cells. S1P generated by Sphk2 binds to and inhibits histone deacetylase (HDAC) activity
and enhances gene expression. Recently Spns2 has been identified as an S1P export pathway; inhibition of
S1P transport increases cytoplasmic S1P and inhibits production of fibrogenic factors in cultured kidney cells,
and Spns2 deficient mice are associated with inflammatory disease conditions. Spns2 is highly expressed in
proximal tubule, endothelium and pericytes. Lastly we found that a lead Spns2 inhibitor attenuated AKI. These
findings lead us to hypothesize that compartmental control of S1P is a critical determinant of progressive
kidney fibrosis. Aim 1 will test the hypothesis that nuclear Sphk2-deficiency protects mice from kidney fibrosis.
We will determine whether the enzymatic activity or the nuclear localization of Sphk2 are necessary for fibrosis.
Aim 2 will test the hypothesis that Spns2 inhibition or Spns2 deficiency protects mice from progressive kidney
fibrosis. We will determine whether 1) global Spns2 deficient mice are protected from fibrosis and 2) mice treated
with a lead Spns2 inhibitor, are protected from fibrosis. Aim 3. Will test the hypothesis that control of kidney
parenchymal export of S1P is critical in attenuating fibrosis. We hypothesize that the protective effect is due to
decreased export of S1P in proximal tubule cells, endothelial cells or pericytes. We will generate pericyte,
endothelial and proximal tubule Spns2-/- mice and determine the effect on fibrosis. We will perform in vitro studies
and determine the role of compartmental control of S1P pericytes, endothelial cells or proximal tubule cells
factors th...

## Key facts

- **NIH application ID:** 9972349
- **Project number:** 2R01DK085259-09
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Mark Douglas Okusa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,020
- **Award type:** 2
- **Project period:** 2010-03-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972349

## Citation

> US National Institutes of Health, RePORTER application 9972349, Sphingolipids in Acute Kidney Injury and Disease Progression (2R01DK085259-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972349. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*