Significance of Epac signaling in renal Na+ handling and hypertension

Epac 信号在肾钠处理和高血压中的意义

• 批准号: 10864073
• 负责人: XIAODONG CHENG
• 金额: $ 15万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10864073
• 关键词: Address; Adverse effects; Animal Model; Antihypertensive Agents; Automobile Driving; Binding; Biological Availability; Biology; Blood Pressure; Body Water; Clinical; Collaborations; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Diet; Diuretics; Duct (organ) structure; Electrolytes; Electrophysiology (science); Epithelium; Equilibrium; Excretory function; Exhibits; G-Protein-Coupled Receptors; Genes; Genetic Models; Homeostasis; Hormones; Human; Hypertension; Hypotension; Hypovolemia; Hypovolemics; Imaging Device; Impairment; Individual; Intake; Kidney; Laboratories; Link; Mediating; Mitochondria; Molecular; Molecular Target; Mus; Natriuresis; Nephrons; Ontology; Oxidative Stress; Pathology; Pathway interactions; Pattern; Pharmacology; Physiological; Physiology; Play; Preparation; Process; Production; Protein Isoforms; Proteins; Publishing; Reactive Oxygen Species; Regulation; Renal function; Renal tubule structure; Rodent; Rodent Model; Role; Scheme; Signal Transduction; Sodium; Sodium Chloride; System; Testing; Toxic effect; Tubular formation; Variant; Water; absorption; blood pressure control; blood pressure elevation; blood pressure reduction; clinically significant; dietary; dietary salt; drug discovery; epithelial Na+ channel; fighting; hyperkalemia; hypertension treatment; hypertensive; improved; in vivo; inhibitor; membrane activity; mouse model; novel; pharmacologic; response; salt balance; salt intake; saluretic; small molecule; sodium-hydrogen exchanger 3; synergism; therapeutic target; therapeutically effective; tool; transcriptome sequencing; urinary

PROJECT SUMMARY Kidneys play a central role in regulation of water-salt balance with excessive renal Na+ conservation being tightly associated with hypertension. The existing diuretics inhibit Na+ reabsorption in individual renal tubule segments, which often involves a compensatory response in other segments to limit their efficiency. Thus, targeting Na+ transporting systems in multiple segments simultaneously might represent a more effective way to fight hypertension. Our groups generated abundant multicomponent evidence that exchange protein directly activated by cAMP (Epac) isoforms 1 and 2 are critical regulators of renal Na+ handling in the proximal tubule (PT) and the collecting duct (CD). Epac1 and Epac2 deletion compromises renal Na+ conservation in mice, leading to reduced blood pressure during dietary Na+ restriction. This is associated with decreased activity and expression of the sodium hydrogen exchanger-3 (NHE-3) in PT and epithelial Na+ channel (ENaC) in CD. Furthermore, RNAseq Gene Ontology enrichment analysis revealed an improvement of mitochondria function and reduction in the reactive oxygen species (ROS) production in PT and CD upon Epac deletion. Interestingly, renal Epac expression is drastically increased during hypertension arguing for deleterious ramifications of Epac over-activation in driving Na+ retention and the development of elevated blood pressure. To this end, we have developed novel pharmacological tools to selectively inhibit Epac isoform(s), and observed natriuretic actions of these small molecules while exhibiting low toxicity and potent bioavailability profiles. Overall, we hypothesize that Epac1 and Epac2 isoforms are physiologically relevant regulators of sodium reabsorption in both PT and CD in response to hypovolemia. On the contrary, over-activation of Epac cascade contributes significantly to the development of renal sodium retention and hypertension, in part by increasing ROS production and oxidative stress. We propose that pharmacological inhibition of Epac signaling could be a novel, potent, and safe strategy to counteract hypertension and improve renal function. We plan to test this with 3 specific aims: SA1. Determine salt-sensitivity associated with Epac-induced changes on tubular transport in mice lacking Epac isoforms to establish roles of renal and extra-renal components of Epac signaling. SA2. Examine the molecular targets and signaling mechanisms of Epac-dependent regulation of Na+ transport in the PT and CD. SA3. To test the hypothesis that Epac1 and 2 are effective therapeutic targets of hypertension using optimized Epac specific inhibitors. In summary, we develop this proposal by merging highly complementary and synergistic expertise in renal physiology/epithelial transport and Epac signaling/drug discovery from neighboring laboratories of Dr. Pochynyuk and Dr. Cheng within the Department of Integrative Biology and Pharmacology, UTHSC at Houston. We anticipate to uncover previously unrecognized physiologically relevant means of Epac signaling in the kidney and to establish the pharmacological potential of Epac blockade in treatment of hypertension.

项目总结