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Renal sphingosine-1-phosphate receptor 1 in salt-sensitive hypertension

盐敏感性高血压中的肾 1-磷酸鞘氨醇受体 1

基本信息

批准号：
10319594
负责人：
Ningjun Li
金额：
$ 38.71万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-18 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319594
关键词：
Acetates Agonist Aldosterone Antihypertensive Agents Attenuated Blood Vessels Cardiovascular Diseases Cardiovascular system Cell membrane Cell physiology Cells Coupled Cyclic AMP Data Deoxycorticosterone Development Disease Diuretics Dose Duct (organ) structure Elements Excretory function Family Functional disorder G-Protein-Coupled Receptors H218 Protein Homeostasis Hypertension Impairment Infusion procedures Kidney Kidney Diseases Knock-out Knockout Mice Lipids Lung Lymphoid Mediating Molecular Mus Natriuresis Pathogenesis Pathology Pathway interactions Pharmacology Phosphorylation Physiology Play Protein Isoforms Proteins Regulation Renal function Reporting Role Signal Pathway Signal Transduction Signaling Molecule Sodium Sphingolipids Sphingosine Sphingosine-1-Phosphate Receptor System Testing Transgenes Tubular formation base blood pressure control body system brain tissue edg-3 Protein epithelial Na+ channel experimental study high salt diet hypertensive insight ischemic injury kidney medulla member novel novel therapeutics overexpression patch clamp pressure protective effect receptor salt intake salt sensitive hypertension saluretic sphingosine 1-phosphate sphingosine kinase

项目摘要

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.

鞘脂最初被认为是细胞膜的沉默结构元件。最近，鞘脂代谢物正在成为重要的脂质信号分子。其中，鞘氨醇-1- 已知磷酸盐 (S1P) 在各种器官系统的细胞过程中发挥重要作用，包括心血管系统和肾脏。 S1P 受体家族 (S1P1–S1P5) 的五个成员已被确定。 S1P1-3受体广泛表达，而S1P4则存在于肺和淋巴系统中， S1P5主要存在于脑组织中。 S1P1-3 受体存在于肾脏中。事实证明，S1P 系统在许多疾病的发病机制中发挥着重要作用，包括心血管和肾脏疾病疾病。值得注意的是，肾脏中的三种 S1P 受体的功能是不同的。 S1P1介导保护性影响，而 S1P2 和 S1P3 介导对肾脏的损害作用。尽管许多报道显示 S1P 通路参与肾脏生理和病理，但对肾脏 S1P 的作用知之甚少 Na+排泄系统。我们最近证明 S1P1-3 受体在肾髓质，主要位于集合管，肾髓质中的S1P1受体介导通过抑制上皮 Na+ 通道 (ENaC) 产生强烈的利尿钠作用。我们的初步数据显示，高盐摄入量上调了肾髓质中 S1P1 的水平，有趣的是，醋酸脱氧皮质酮 (DOCA) 治疗显着降低了肾髓质中的 S1P1 水平。在有集合管的小鼠中 (CD) 特异性 S1P1 敲除 (KO)，压力尿钠排泄减弱，高盐摄入量促进更多 Na+ 保留与对照小鼠相比。此外，高盐摄入会导致盐敏感性高血压当用低剂量的 DOCA 治疗时，CD 特异性 S1P1 KO 小鼠出现这种情况，但对照小鼠却没有这种情况。上另一方面，局部输注 BAF312（一种选择性 S1P1 激动剂）到肾髓质的效果显着减弱 DOCA-盐高血压。基于这些发现，我们假设肾髓质 S1P1 通路是一条抑制过度 Na+ 重吸收和抑制肾功能的关键平衡机制髓质 S1P1 通路有助于盐敏感性高血压的发生。三个具体目标是建议检验我们的假设。目的 1：确定肾脏中 S1P1 通路的抑制是否髓质有助于盐敏感性高血压的发病机制。 CD 特异性缺失 S1P1 的小鼠或将使用 S1P1 转基因的 CD 特异性过表达。目标2：确定S1P1通路是否抑制ENaC活性，从而增加Na+排泄，发挥降压作用。膜片钳将进行新分离的集合管中 ENaC 通道活性的研究。目标3：探索 S1P1激活抑制ENaC活性通过Gi发挥降压作用的机制蛋白质/cAMP 偶联信号传导。拟议的研究将揭示肾 Na+ 的新分子机制处理盐敏感性高血压的发病机制并提供新的见解。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis.

DOI：
10.1016/j.bbadis.2022.166456
发表时间：
2022-10-01
期刊：
Biochimica et biophysica acta. Molecular basis of disease
影响因子：
0
作者：
通讯作者：

Mechanism of Diuresis and Natriuresis by Cannabinoids: Evidence for Inhibition of Na+-K+-ATPase in Mouse Kidney Thick Ascending Limb Tubules.

大麻素的利尿和尿钠排泄机制：抑制小鼠肾升肢粗管中 Na -K -ATP 酶的证据。

DOI：
10.1124/jpet.120.000163
发表时间：
2021
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
0
作者：
Ritter,JosephK;Ahmad,Ashfaq;Mummalaneni,Shobha;Daneva,Zdravka;Dempsey,SaraK;Li,Ningjun;Li,Pin-Lan;Lyall,Vijay
通讯作者：
Lyall,Vijay

Inhibitory effects of growth differentiation factor 11 on autophagy deficiency-induced dedifferentiation of arterial smooth muscle cells.