# Renal acid ceramidase-S1P pathway in salt-sensitive hypertension

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $467,473

## Abstract

Sphingolipid metabolites are recently emerging as important lipid signaling molecules. Among them,
sphingosine-1-phosphate (S1P) is known to play critical roles in cellular processes in various organ systems
including kidneys. S1P receptor (S1PR)1, S1PR2 and S1PR3 as well as S1P-producing enzymes are detected
in the kidneys. S1P system plays important roles in the pathogenesis of many kidney diseases. However, little
is known about the role of the S1P system in renal Na+ excretion. We have recently shown that S1P receptors
are prominently expressed in the renal medulla; S1P is a novel diuretic factor in the renal medulla and regulates
Na+ excretion via the activation of S1PR1 receptor; S1PR1 in collecting duct is an important antihypertensive
pathway by promoting sodium excretion and that impairment of renal medullary S1PR1 contributes to salt-
sensitive hypertension. These studies suggest important roles of renal S1P system in salt-sensitive hypertension.
Our previous studies focused on S1PR1 receptor. Apparently, levels of S1P production would play critical roles
in the function of S1P system. However, whether enzymes that produce S1P participate in the control of Na+
excretion and blood pressure has not been investigated. Our preliminary studies demonstrated that among the
enzymes that are responsible for the S1P production, acid ceramidase (AC) as the rate-limit enzyme was
significantly increased after high salt intake and inhibited in DOCA-salt hypertension. Moreover, infusion of AC
inhibitor into renal medulla and knockout of AC in collecting ducts inhibited sodium excretion and increased salt
sensitivity of blood pressure. Based on the above information, the central hypothesis is that high salt-induced
AC-S1P pathway in the renal medulla is a novel mechanism to promote the excretion of extra Na+ load and that
suppression of renal medullary AC-S1P pathway contributes to the development of salt-sensitive hypertension.
Mechanistically, we characterized the expressions of candidate transcription factors and found that Activating
Protein 2α (AP2A) was increased after high salt intake and present in the collecting ducts. It is therefore proposed
that AP2A is the upstream signal to activate the expression of AC. Indeed, our preliminary data showed that
transfection of AP2A shRNA into the renal medulla blocked the high salt-induced AC expression and that the
high salt-induced AP2A was suppressed in DOCA-salt mice. Three specific aims are proposed. Aim 1: To test
the hypothesis that activation of AC-S1P pathway mediates the excretion of extra sodium load and that inhibition
of AC-S1P pathway in the renal medulla impairs renal Na+ handling, thereby enhancing salt sensitivity of blood
pressure. Aim 2: To test the hypothesis that the deficiency of AC-S1P pathway contributes to the pathogenesis
of salt-sensitive hypertension in DOCA-salt model. Aim 3: To determine the mechanisms causing the deficiency
of AC pathway: test the hypothesis that impairment ...

## Key facts

- **NIH application ID:** 10943173
- **Project number:** 1R01DK140219-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Ningjun Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,473
- **Award type:** 1
- **Project period:** 2024-08-07 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943173

## Citation

> US National Institutes of Health, RePORTER application 10943173, Renal acid ceramidase-S1P pathway in salt-sensitive hypertension (1R01DK140219-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10943173. Licensed CC0.

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