# Sphingosine-1-phosphate in renal microvascular dysfunction of ischemia-reperfusion kidney injury

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $356,060

## Abstract

Renal ischemia-reperfusion (IR) is a leading cause of acute kidney injury (IR-AKI), a significant unsolved
clinical problem. A critical barrier to progress with IR-AKI is that there are gaps in our scientific
understanding of the mechanisms underlying the persistent reduction of medullary blood flow (MBF), a key
factor determining the outcome of IR-AKI and the progression to chronic kidney disease (CKD). Our goal is to
address this critical barrier by focusing on the role of sphingosine-1-phosphate (S1P) as a potential signaling
molecule contributing to renal microvascular dysfunction in IR-AKI. Our central hypothesis is that renal
ischemia-reperfusion leads to significantly enhanced sensitivity of juxtamedullary afferent arterioles, the crucial
vascular segment that controls MBF, to S1P-mediated vasoconstriction which contributes to a persistent
reduction of MBF and a steady decline in glomerular filtration rate (GFR) in IR-AKI. Our objectives are to
address this central hypothesis by (1) determining the role of S1P in controlling juxtamedullary afferent
arteriolar function and renal hemodynamics in IR-AKI; (2) establishing the cellular mechanisms of S1P-
dependent regulation of afferent arteriolar reactivity in IR-AKI; and (3) determining the pathophysiological role
of S1P in the development of renal microvascular dysfunction in IR-AKI. We will test this central hypothesis
through three specific aims. AIM 1 will test the hypothesis that renal ischemia-reperfusion leads to enhanced
sensitivity of afferent arterioles to S1P which contributes to a persistent vasoconstriction and reduction of MBF
in IR-AKI. AIM 2 will test the hypothesis that the renal ischemia-reperfusion-induced increase in reactive
oxygen species production contributes to enhanced S1P sensitivity of afferent arterioles in IR-AKI. AIM 3 will
test the hypothesis that inhibition of S1P receptor activation prevents enhancement of S1P-mediated afferent
arteriolar vasoconstriction during ischemia-reperfusion and protects against IR-AKI. We will use the in vitro
blood-perfused juxtamedullary nephron technique to assess the impact of IR on S1P-mediated arteriolar
response in rats and in S1P2 receptor knockout mice. We will determine the influence of S1P on total and
regional renal blood flow and GFR with IR-AKI. We will determine which S1P receptors contribute to enhanced
S1P-mediated vasoconstriction. We will measure sphingolipid metabolites in kidney and plasma of IR rats or
mice. Our outcomes will provide new mechanistic insights that renal IR activates the S1P signaling pathway
in the renal microvasculature. Exogenous S1P causes potent vasoconstriction of afferent arterioles and
reduction of renal blood flow and MBF, which will be enhanced in IR-AKI. S1P2 receptor blockade or deletion
will protect against IR-AKI. The results of this study will improve our understanding of the pathophysiological
mechanisms underlying the persistent reduction of MBF and a steady decline in GFR in IR-A...

## Key facts

- **NIH application ID:** 9937726
- **Project number:** 5R01DK106500-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Zhengrong Guan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,060
- **Award type:** 5
- **Project period:** 2017-07-18 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937726

## Citation

> US National Institutes of Health, RePORTER application 9937726, Sphingosine-1-phosphate in renal microvascular dysfunction of ischemia-reperfusion kidney injury (5R01DK106500-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9937726. Licensed CC0.

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