The circadian clock protein BMAL and post-translational regulation of ENaC in the kidney

肾脏中生物钟蛋白 BMAL 和 ENaC 的翻译后调节

• 批准号: 10202590
• 负责人: Abdel Ayube Alli
• 金额: $ 33.55万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202590
• 关键词: ARNTL gene; Adaptor Signaling Protein; Address; Aldosterone; Antihypertensive Agents; Apical; Attenuated; Binding; Biological Assay; Biotinylation; Blood Pressure; Cardiovascular Diseases; Caspase; Cathepsins B; Cause of Death; Cell membrane; Cells; Clock protein; Data; Distal; Duct (organ) structure; Ductal Epithelial Cell; Electrolytes; Equilibrium; Essential Hypertension; Etiology; Excretory function; Exhibits; Female; Fluorescence Resonance Energy Transfer; Genes; Goals; Grant; Hour; In Situ; Infusion procedures; Investigation; Ion Channel; Kidney; Knockout Mice; Knowledge; Lead; MARCKS gene; Mass Spectrum Analysis; Measures; Mediating; Membrane; Metabolic; Molecular; Mus; Nephrons; Patch-Clamp Techniques; Pathogenesis; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Play; Post-Translational Protein Processing; Post-Translational Regulation; Potassium; Probability; Proteins; Proteolysis; Proteome; Proteomics; Regulation; Role; Sex Differences; Sodium; Telemetry; Testing; Time; United States; Up-Regulation; Western Blotting; Wild Type Mouse; alpha 1-Antitrypsin; apical membrane; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; circadian; circadian pacemaker; circadian regulation; density; epithelial Na+ channel; experimental study; male; new therapeutic target; novel; overexpression; protein expression; renal epithelium; salt balance; sodium channel proteins; targeted treatment; transcription factor; urinary

ABSTRACT The epithelial sodium channel (ENaC) expressed in the distal tubule and collecting duct is responsible for the final regulation of sodium reabsorption by the kidneys. The myristoylated alanine-rich C kinase substrate (MARCKS) plays an important role as an adaptor protein between the anionic phospholipid PIP2 and ENaC. Both ENaC and MARCKS are positively regulated by the protease cathepsin B. First, our preliminary data demonstrate renal ENaC activity and MARCKS protein expression are positively regulated by the circadian protein BMAL1. Second, our preliminary data show alpha-1 antitrypsin is increased in the BMAL1 knockout mouse kidney compared to the kidney of wild-type mice sacrificed at the same time. Third, our preliminary data show alpha-1 antitrypsin is expressed in the kidney and it strongly inhibits cathepsin B activity and contributes to blood pressure regulation. In this project we will test our hypothesis that the association between renal ENaC and MARCKS, and their function at the apical plasma membrane negatively correlates with alpha-1 antitrypsin expression in a circadian dependent manner. We will perform experiments to investigate proteolysis and apical membrane expression of ENaC and MARCKS, ENaC activity, sodium handling, and blood pressure using male and female BMAL1 knockout mice, alpha-1 antitrypsin knockout mice, alpha-1 antitrypsin overexpressing mice, cathepsin B knockout mice, and wild-type control mice. The successful completion of our proposed studies for this project will reveal new mechanisms underlying the role of BMAL1 in the regulation of renal ENaC and MARCKS and blood pressure control. Our long term goal is to provide a better understanding for the pathogenesis of essential hypertension that can potentially lead to novel drug targets and therapeutics.

摘要