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，对公众健康有着重要的影响，但其基本发病机制尚未完全清楚，需要新的治疗靶点。前列腺素类在高血压中的有益作用被认为是因为非甾体抗炎药（NSAID），它阻断所有前列腺素类的产生，可导致钠潴留和加重高血压。在前列腺素类中，PGE 2及其EP 4受体（EP 4 R）与血压控制有关，但这些机制尚不清楚。我们以前的工作表明，在成年小鼠的所有组织中，EP 4 R的条件性缺失显著加剧了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EP 4 R对高血压的发展没有影响。相比之下，从整个肾上皮特异性去除EP 4 R概括了加重的高血压的表型，表明EP 4 R通过在肾上皮中的直接作用来减弱高血压。最近的单细胞测序研究表明，在肾上皮细胞中的EP 4 R表达富集在集合管（CD）。CD通过上皮钠通道（ENaC）的作用在最终尿钠排泄中发挥关键作用。我们的初步研究表明，在整个肾单位的肾上皮细胞中的EP 4 R缺失的小鼠对ENaC抑制剂的反应性增加，并且PGE 2抑制分离的CD中的ENaC活性。因此，我们假设EP 4 R通过在CD中的作用来抵抗高血压的发展，以减少经由ENaC的钠重吸收。该项目的目标是确定EP 4 R抗高血压作用的潜在机制，并将其用于人类高血压的新治疗。我们的目的是：1）确定肾上皮细胞中EP 4 R作用的细胞特异性以抵抗高血压。我们将分别产生从整个CD、主细胞或嵌入细胞中缺失EP 4 R的小鼠，以评估这些遗传改变对血压、钠稳态和高血压中ENaC功能的影响; 2）确定EP 4 R调节ENaC的机制。我们将在分离的CD中进行膜片钳电生理学，以表征介导其对减轻高血压发展的强大作用的EP 4 R下游信号通路。该研究的成功完成有望确定EP 4 R抗高血压作用的机制。长期目标是确定原发性高血压的新治疗靶点。

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.