Sphingolipids were originally thought to serve as silent structural elements of the cell membrane. Recently, sphingolipid metabolites are emerging as important lipid signaling molecules. Among them, sphingosine-1- phosphate (S1P) is known to play important roles in cellular processes in various organ systems including the cardiovascular system and kidney. Five members of the S1P receptor family (S1P1?S1P5) have been identified. The S1P1-3 receptors are ubiquitously expressed, while S1P4 is in the lung and lymphoid system, and S1P5 mainly in brain tissue. The S1P1-3 receptors are present in the kidneys. It has been shown that S1P system plays a significant role in the pathogenesis of many diseases, including cardiovascular and kidney diseases. Notably, the functions of three S1P receptors in the kidneys are different. S1P1 mediates protective effects, whereas S1P2 and S1P3 mediate injurious effect in the kidneys. Despite many reports showing the involvement of S1P pathway in renal physiology and pathology, little is known about the role of renal S1P system in Na+ excretion. We have recently demonstrated that S1P1-3 receptors are prominently expressed in the renal medulla, mainly located in the collecting ducts, and that S1P1 receptor in the renal medulla mediates a strong natriuretic effect via inhibiting epithelial Na+ channel (ENaC). Our preliminary data showed that high salt intake upregulated the level of S1P1 in the renal medulla, and interestingly, deoxycorticosterone acetate (DOCA) treatment significantly reduced the level of S1P1 in the renal medulla. In mice with collecting duct (CD)-specific S1P1 knockout (KO), the pressure natriuresis was blunted and high salt intake promoted more Na+ retention compared with control mice. Furthermore, high salt intake produced a salt-sensitive hypertension in CD-specific S1P1 KO mice but not in control mice when treated with a subpressor dose of DOCA. On the other hand, infusion of BAF312, a selective S1P1 agonist, locally into the renal medulla remarkably attenuated DOCA-salt hypertension. Based on these findings, we hypothesize that the renal medullary S1P1 pathway is a critical counterbalancing mechanism to inhibit the excessive Na+ reabsorption and that suppression of renal medullary S1P1 pathway contributes to the development of salt-sensitive hypertension.
Three specific aims are proposed to test our hypothesis.
Aim 1 : To determine whether the suppression of S1P1 pathway in the renal medulla contributes to the pathogenesis of salt-sensitive hypertension. Mice with CD-specific deletion of S1P1 or CD-specific overexpression of S1P1 transgene will be used.
Aim 2 : To determine whether S1P1 pathway inhibits ENaC activity and thereby increases Na+ excretion, exerting the antihypertensive action. Patch clamp studies of ENaC channel activity in freshly isolated collecting ducts will be performed.
Aim 3 : To explore the mechanism by which S1P1 activation inhibits ENaC activity to exert antihypertensive action via Gi protein/cAMP-coupled signaling. The proposed studies will reveal a novel molecular mechanism in renal Na+ handling and provide new insights into the pathogenesis of salt-sensitive hypertension.

Public Health Relevance

The high salt diet stimulates the expression of renal sphingosine-1-phosphate receptor 1 (S1P1), which increases the excretion of extra sodium load. Dysfunction of the S1P1 signaling pathway promotes sodium retention and causes high blood pressure. Clarification of this mechanism may ultimately suggest new therapies associated with enhancing S1P1 function for the treatment of high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL145163-03
Application #
10064007
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Varagic, Jasmina
Project Start
2019-01-18
Project End
2022-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298