The role of kidney epithelial cells specific EP4 receptors in blood pressure control

肾上皮细胞特异性EP4受体在血压控制中的作用

• 批准号: 10709597
• 负责人: Ting Yang
• 金额: $ 29.09万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709597
• 关键词: Adult; Affect; American; Amiloride; Antihypertensive Agents; Area; Attenuated; Blood Pressure; Cells; Cessation of life; Chronic Disease; Clinical Research; Complex; Cyclic AMP; Development; Dinoprostone; Diuretics; Drug Receptors; Duct (organ) structure; Ductal Epithelium; EP4 receptor; Electrophysiology (science); Endothelial Cells; Epithelium; Essential Hypertension; Excision; Excretory function; Goals; Homeostasis; Human; Hypertension; Individual; Intercalated Cell; Kidney; Knowledge; Lead; Link; MAP Kinase Gene; Macrophage; Mediating; Morbidity - disease rate; Mus; Mutation; Natriuresis; Nephrons; Non-Steroidal Anti-Inflammatory Agents; PIK3CG gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Production; Prostaglandins; Protein Kinase C; Public Health; Quality of life; Receptor Inhibition; Regulation; Renal tubule structure; Renin-Angiotensin System; Research; Resistance; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Sodium; Specificity; Techniques; Testing; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Vascular Smooth Muscle; WFDC2 gene; Work; absorption; antagonist; blood pressure control; blood pressure elevation; blood pressure reduction; candidate identification; cardiovascular effects; cellular targeting; epithelial Na+ channel; genetic approach; hypertensive; inhibitor; kidney epithelial cell; mortality; new therapeutic target; novel strategies; patch clamp; preservation; protein kinase C kinase; receptor expression; renal epithelium; response; single cell sequencing; single-cell RNA sequencing; urinary; vacuolar H+-ATPase

Hypertension is a common chronic disease with a significant impact on public health, yet its basic pathogenesis is not fully understood, and new therapeutic targets are needed. A beneficial role for prostanoids in hypertension was suggested because non-steroidal anti-inflammatory drugs (NSAIDs), which block the production of all prostanoids, can cause sodium retention and exacerbate hypertension. Among prostanoids, PGE2 and its EP4 receptor (EP4R) have been implicated in blood pressure control, but these mechanisms are unknown. Our previous work showed that conditional deletion of EP4R from all tissues in adult mice dramatically exacerbated Ang II-dependent hypertension. However, the elimination of EP4R from vascular smooth muscle cells, endothelial cells, and macrophages had no impact on hypertension development. By contrast, specific removal of EP4R from whole renal epithelia recapitulated the phenotype of exacerbated hypertension, indicating that EP4R attenuates hypertension by direct actions in the renal epithelium. Recent single-cell sequencing studies demonstrated that EP4R expression in renal epithelia is enriched in the collecting duct (CD). CDs have pivotal roles in final urinary sodium excretion through the actions of the epithelial sodium channel (ENaC). Our preliminary studies showed that mice with EP4R deletion in renal epithelia throughout the nephron had increased responsiveness to ENaC inhibitor, and PGE2 inhibits the ENaC activity in isolated CDs. Thus, we hypothesize that EP4R resists the development of hypertension through actions in the CD to reduce sodium reabsorption via ENaC. The project’s objective is to identify mechanisms underlying the anti-hypertension effects of EP4R and to exploit them for new treatments of human hypertension. Our Aims are: 1) Identify cell specificity for EP4R actions in kidney epithelia to resist hypertension. We will generate mice with EP4R deleted from entire CDs, principal cells, or intercalated cells, respectively, to assess the consequences of these genetic alterations on blood pressure, sodium homeostasis, and ENaC function in hypertension; and 2) Determine the mechanisms of ENaC regulation by EP4R. We will perform patch-clamp electrophysiology in isolated CDs to characterize EP4R downstream signaling pathways that mediate its powerful effects on attenuating the development of hypertension. Successful completion of the proposed research is expected to identify the mechanisms underlying the antihypertensive actions of EP4R. The long-term goal is to identify novel therapeutic targets for essential hypertension.

高血压是一种常见的慢性疾病，对公共卫生有重大影响，但尚未完全了解其基本的发病机理，需要新的治疗靶标。提出了前列腺素在高血压中的有益作用，因为非甾体类抗炎药（NSAIDS）阻止了所有前列腺素的产生，可能会导致钠保留率并加剧高血压。在前列腺素中，PGE2及其EP4受体（EP4R）已在血压控制中浸渍，但这些机制尚不清楚。我们以前的工作表明，成年小鼠中所有组织中EP4R的有条件缺失，动态加剧了ANG II依赖性高血压。然而，从血管平滑肌细胞，内皮细胞和巨噬细胞中消除EP4R对高血压发育没有影响。相比之下，从整个肾上皮中对EP4R的特异性去除概括了加重高血压的表型，表明EP4R通过肾上皮中的直接作用减轻了高血压。最近的单细胞测序研究表明，肾上皮中的EP4R表达富含收集管（CD）。 CD通过上皮钠通道（ENAC）的作用在最终尿钠排泄中具有关键作用。我们的初步研究表明，整个肾单位中肾上皮中EP4R缺失的小鼠对ENAC抑制剂的反应性增加，PGE2抑制了分离的CD中的ENAC活性。这就是我们假设EP4R通过CD中的作用来抑制高血压的发展，从而减少通过ENAC减少钠的重吸收。该项目的目标是确定EP4R抗高血压作用的基础机制，并将其利用为人类高血压的新疗法。我们的目的是：1）确定肾上皮中EP4R作用的细胞特异性以抵抗高血压。我们将分别从整个CD，主要细胞或插入细胞中删除的EP4R产生小鼠，以评估这些遗传改变对血压，稳态钠和ENAC功能的后果； 2）确定EP4R的ENAC调节的机制。我们将在孤立的CD中执行斑板钳电生理学，以表征EP4R下游信号传导途径，以介导其对减轻高血压发育的强大影响。预计拟议的研究的成功完成将确定EP4R降压作用的基础机制。长期目标是确定基本高血压的新型治疗靶标。

项目成果

Cell-Specific Actions of the Prostaglandin E-Prostanoid Receptor 4 Attenuating Hypertension: A Dominant Role for Kidney Epithelial Cells Compared With Macrophages.

• DOI: 10.1161/jaha.122.026581
• 发表时间: 2022-10-04
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Yang, Ting;Song, Chengcheng;Ralph, Donna L.;Andrews, Portia;Sparks, Matthew A.;Koller, Beverly H.;McDonough, Alicia A.;Coffman, Thomas M.
• 通讯作者: Coffman, Thomas M.