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

项目总结 已知调节高血压(BP)和肾脏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 肾脏疾病的定义也不是很好。关键的调节因子是心房利钠多肽(ANP， BNP)，通过利钠肽受体A(NPRA)和第二信使cGMP传递信号。有一个 编码ANP(NPPA)、BNP(NPPB)和NPRA(Npr1)的基因具有很强的多态关联 患有高血压和心血管疾病的人。目前还不清楚在特定细胞中缺乏Npr1是如何- 肾脏的类型可能会逐渐导致高血压和肾脏疾病，也不是性别差异的基础 疾病病因的差异。涉及转录因子的遗传和表观遗传机制 (TFS)和修改的组蛋白密码，分别调节高血压和肾脏损伤的发病机制 和功能障碍还没有得到很好的理解。初步和公布的结果提供了耐人寻味的 视黄酸受体-α(RAR-α)激动剂促进NPr1和NPr1转录和表达的证据 受体信号转导；然而，血管紧张素II和转化生长因子-β1(转化生长因子-β1)抑制 原代培养肾细胞中NPr1的转录和受体功能。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 转录因子和组蛋白密码的作用；然而，它们在调控基因转录和信号转导中的作用 高血压和肾脏疾病还没有得到很好的了解。目前提案的总体目标是 确定荷尔蒙控制机制如何影响控制疾病的遗传和表观遗传因素 NPr1及其受体的功能，以性别特异性的方式调节高血压和肾脏损伤和功能障碍。这个 中心假说是Npr1的表达和受体信号是由遗传和 表观遗传机制，以及肾小管和足细胞中细胞特异性Npr1的丢失将触发 高血压和肾脏损伤及紊乱。提出的具体目标将检验假设：1)确定 抑制Npr1表达和受体信号转导导致高血压和肾脏损害的机制 紊乱，2)描述了增强Npr1表达和受体信号转导和降低的机制 高血压与肾脏损伤和功能障碍，以及3)描述了影响高血压和肾脏损伤和功能障碍的交互机制 不同的刺激和抑制因子调节高血压和肾脏损伤的范式转换 功能障碍。已完成的研究结果应有助于确定急需的新的 分子生物标记物和治疗在高血压和肾脏疾病防治中的应用 人类特有的性别方式。

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.