ANP Receptor: Genetic and Epigenetic Mechanisms Regulating Blood Pressure and Kidney Injury and Dysfunction

ANP 受体：调节血压和肾损伤和功能障碍的遗传和表观遗传机制

• 批准号: 10512972
• 负责人: Kailash N Pandey
• 金额: $ 46.11万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512972
• 关键词: Abnormal Cell; Adult; Age; Agonist; Angiotensin II; Atrial Natriuretic Factor Receptors; Brain natriuretic peptide; Cardiovascular Diseases; Cells; Cessation of life; Chronic Kidney Failure; Cyclic GMP; Diagnosis; Disease; Epigenetic Process; Etiology; Exhibits; Female; Functional disorder; Gender; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Haplotypes; Heart Atrium; Heart failure; Histone Code; Histones; Hormonal; Hormones; Human; Hypertension; Injury; Injury to Kidney; Kidney; Kidney Diseases; Lead; Mission; Molecular; Molecular Genetics; Molecular Target; Mus; Mutant Strains Mice; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrons; Organ; Pathogenesis; Phenotype; Play; Prevention; Publishing; Receptor Signaling; Renal Hypertension; Research; Role; Second Messenger Systems; Sex Differences; Signal Transduction; TGFB1 gene; Testing; Therapeutic; United States National Institutes of Health; Woman; atrial natriuretic factor receptor A; base; blood pressure regulation; cell determination; cell type; chromatin modification; decubitus ulcer; expectation; improved; in vivo; insight; kidney cell; kidney dysfunction; knockout gene; male; men; molecular marker; mouse model; new therapeutic target; novel; novel marker; podocyte; prevent; receptor expression; receptor function; recruit; renal damage; retinoic acid receptor alpha; sex; tool; transcription factor

PROJECT SUMMARY The mechanisms regulating high blood pressure (BP) and kidney injury and dysfunction are known to have a strong genetic component; however, the specific genes involved in the pathogenesis of hypertension and renal disorders are not well defined. The key regulators are atrial and brain natriuretic peptides (ANP, BNP), signaling through natriuretic peptide receptor-A (NPRA) and the second messenger cGMP. There is a strong association of polymorphisms in the genes that encode ANP (Nppa), BNP (Nppb), and NPRA (Npr1) with high BP and cardiovascular disorders in humans. It is not clear how the lack of Npr1 in the specific cell- types of the kidney might progressively lead to high BP and renal disorders, nor what underlies the sex-specific differences in the disease etiologies. The genetic and epigenetic mechanisms involving transcription factors (TFs) and modified histone codes, respectively, which regulate the pathogenesis of high BP and kidney injury and dysfunction are not well understood. The preliminary and published results have provided the intriguing evidence that retinoic acid receptor-α (RAR-α) agonists enhance the transcription and expression of Npr1 and receptor signaling; however, angiotensin II (Ang II) and transforming growth factor-beta 1 (TGF-β1) repress Npr1 transcription and receptor function in primary cultured renal cells. These stimulating and inhibiting hormones also govern genetic and epigenetic mechanisms of gene expression and regulation by interacting actions of TFs and histone codes; however, their roles in modulating gene transcription and signaling in hypertension and kidney disorders are not well understood. The overall objective of the current proposal is to determine how the hormonal control mechanisms influence the genetic and epigenetic factors that govern the Npr1 and receptor function, regulating high BP and kidney injury and dysfunction in a sex-specific manner. The central hypothesis is that Npr1 expression and receptor signaling is reciprocally regulated by genetic and epigenetic mechanisms, and that the loss of cell-specific Npr1 in nephron tubules and podocytes will trigger high BP and kidney injury and disorders. The proposed specific aims will test the hypotheses: 1) determine the mechanisms that repress Npr1 expression and receptor signaling leading to high BP and kidney damage and disorders, 2) delineate the mechanisms those enhance Npr1 expression and receptor signaling and decrease high BP and kidney injury and dysfunction, and 3) delineate the interactive mechanisms those impact the divergent stimulatory and inhibitory factors regulating the paradigm shift in high BP and kidney injury and dysfunction. The findings of the completed studies should lead to the identification of much-needed new molecular biomarkers and therapies for the treatment and prevention of high BP and kidney diseases in a gender-specific manner in humans.

项目摘要 已知调节高血压（BP）和肾损伤和功能障碍的机制， 有很强的遗传成分;然而，参与高血压发病机制的特定基因 和肾脏疾病没有很好的定义。关键的调节因子是心房和脑钠肽（ANP， BNP），通过利钠肽受体-A（NPRA）和第二信使cGMP进行信号传导。有一个 编码ANP（Nppa）、BNP（Nppb）和NPRA（Npr 1）的基因多态性的强相关性 高血压和心血管疾病。目前尚不清楚特定细胞中Npr 1的缺乏是如何产生的。 肾脏类型可能会逐渐导致高血压和肾脏疾病，也不是性别特异性的基础 疾病病因的差异。转录因子参与的遗传和表观遗传机制 (TFs)和修饰的组蛋白编码，分别调节高血压和肾损伤的发病机制 和功能障碍还不太清楚。初步和已发表的结果提供了有趣的 有证据表明，视黄酸受体-α（RAR-α）激动剂可增强Npr 1的转录和表达， 然而，血管紧张素II（Ang II）和转化生长因子β 1（TGF-β1）抑制 原代培养肾细胞npr 1转录及受体功能的研究。这些刺激和抑制 激素还通过相互作用控制基因表达和调节的遗传和表观遗传机制， 转录因子和组蛋白编码的作用;然而，它们在调节基因转录和信号转导中的作用， 高血压和肾脏疾病还不太清楚。本提案的总体目标是 确定激素控制机制如何影响控制这些激素的遗传和表观遗传因素。 Npr 1和受体功能，以性别特异性方式调节高血压和肾损伤及功能障碍。的 中心假设是Npr 1表达和受体信号传导受遗传和 表观遗传机制，以及肾单位小管和足细胞中细胞特异性Npr 1的丢失将触发 高血压以及肾脏损伤和疾病。提出的具体目标将检验假设：1）确定 抑制Npr 1表达和受体信号传导的机制导致高血压和肾损伤， 2）描述了增强Npr 1表达和受体信号传导以及降低Npr 1表达和受体信号传导的机制。 高血压和肾损伤和功能障碍，和3）描绘的相互作用机制，这些影响 调节高血压和肾损伤中范式转换的发散性刺激和抑制因子， 功能障碍已完成研究的结果应有助于确定急需的新的 用于治疗和预防高血压和肾脏疾病的分子生物标志物和疗法， 在人类中的性别特异性。