Epithelial Sodium Channels in the Supraoptic Vasopressin and Oxytocin Neurons

视上加压素和催产素神经元中的上皮钠通道

• 批准号: 7665045
• 负责人: RYOICHI TERUYAMA
• 金额: $ 8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665045
• 关键词: Address; Affect; Amiloride; Animal Model; Attenuated; Birth; Blood Circulation; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Defect; Development; Epithelial; Genetic; Homeostasis; Hormones; Human; Hypernatremia; Hypertension; Hypotension; Hypothalamic structure; Hypovolemia; Individual; Injection of therapeutic agent; Kidney; Lactation; Literature; Mediating; Membrane Potentials; Mineralocorticoid Receptor; Natriuresis; Neurons; Oxytocin; Patch-Clamp Techniques; Pattern; Physiological; Plasma; Play; Posterior Pituitary Gland; Posterior Pituitary Hormones; Proteins; Rattus; Regulation; Reporting; Research; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Role; Sodium Channel; Vasopressins; Water; analog; antidiuretic; base; benzamil; brain regulatory center; epithelial Na+ channel; magnocellular; paraventricular nucleus; public health relevance; receptor; response; salt sensitive; supraoptic nucleus; voltage

DESCRIPTION (provided by applicant): The neurohypophysial hormones vasopressin (VP) and oxytocin (OT) are synthesized in the magnocellular neurons (MNCs) located within the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus, and released from the neurohypophysis into the general circulation in response to physiological demands. The secretion of VP increases in response to hyperosmolality, hypovolemia, and hypotension, and produces antidiuretic and pressor effects (Sladek 2000). In addition to the well known effects of OT during parturition and lactation, plasma OT increases in response to hypernatremia (Huang et al., 1995) and induces natriuresis (Conrad et al., 1986; Huang et al., 1994). The non-voltage-dependent, amiloride-sensitive Epithelial Na+ channels (ENaCs) are present in kidney and are known to contribute to Na+ and water homeostasis (Benos et al., 1995). In humans, most of the known genetic causes of hypertension are due to defects in ENaC itself or its regulation, which results in abnormal increases in renal Na+ reabsorption (Dahlberg et al., 2007; Lifton 1996; Mune et al., 1995; Shimkets et al., 1994; Zhou et al., 2007). Interestingly, both messengers and proteins for all three ENaC subunits (1, 2, and 3) have been demonstrated in the cardiovascular regulatory centers of the rat brain including the MNCs in the SON and PVN (Amin et al., 2005). Intracerebroventricular injections of the ENaC blocker, the amiloride analogue benzamil, significantly attenuated the hypertension in animal models with salt-dependent forms of hypertension (Gomez-Sanchez and Gomez-Sanchez 1995; Nishimura et al., 1998). In addition, a known target for altered ENaC expression, the mineralocorticoid receptor (MR), is present in MNCs (Amin et al., 2005). These findings suggest central ENaC inhibition may be a potential new target in the treatment of cardiovascular disease (Teiwes and Toto 2007). Despite these findings, the functional significance of ENaCs and their regulation by MRs in MNCs is completely unknown. Therefore, the overall objective of this research project is to characterize the functional significance of ENaCs in MNCs. We hypothesize that ENaCs affect the firing patterns of VP and OT neurons that ultimately affect the secretion of these hormones, and abnormal expression/regulation of ENaCs in these neurons contributes, at least partly, to abnormal secretion of VP and/or OT in salt-sensitive individuals. To address this hypothesis, we will employ whole-cell patch clamp technique combined with single-cell RT-PCR and immunocytochemisry to determine: 1) the presence and electrophysiological characteristics of ENaC-mediated current in VP and OT neurons; 2) whether abnormal expression/regulation of ENaCs in VP and OT neurons is observed in an animal model of the salt-sensitive rat. PUBLIC HEALTH RELEVANCE Epithelial sodium channels which present in kidney and which play an important role in development of hypertension in human, have been also found in the cardiovascular regulatory centers of the brain vasopressin (VP) and oxytocin (OT) neurons in the hypothalamus. While the brain ENaC may be a potential new target in the treatment of cardiovascular disease, the functional significance of ENaCs in VP and OT neurons is unknown. The research in this proposal will elucidate this critical mechanism, and will increase our ability to manage hypertension.

描述（由申请人提供）：神经垂体激素加压素 (VP) 和催产素 (OT) 在位于下丘脑室旁核 (PVN) 和视上核 (SON) 内的大细胞神经元 (MNC) 中合成，并响应生理反应从神经垂体释放到体循环中。 要求。 VP 的分泌因渗透压过高、血容量不足和低血压而增加，并产生抗利尿和升压作用 (Sladek 2000)。除了众所周知的分娩和哺乳期间 OT 的影响外，血浆 OT 还会因高钠血症而增加（Huang 等，1995）并诱导尿钠排泄（Conrad 等，1986；Huang 等，1994）。非电压依赖性阿米洛利敏感上皮 Na+ 通道 (ENaC) 存在于肾脏中，已知有助于 Na+ 和水的稳态（Benos 等，1995）。在人类中，大多数已知的高血压遗传原因是由于 ENaC 本身或其调节缺陷，导致肾脏 Na+ 重吸收异常增加（Dahlberg et al., 2007; Lifton 1996; Mune et al., 1995; Shimkets et al., 1994; Zhou et al., 2007）。有趣的是，所有三个 ENaC 亚基（1、2 和 3）的信使和蛋白质均已在大鼠大脑的心血管调节中心（包括 SON 和 PVN 中的 MNC）中得到证实（Amin 等，2005）。脑室内注射 ENaC 阻滞剂阿米洛利类似物苯扎米尔，可显着减轻盐依赖性高血压动物模型中的高血压（Gomez-Sanchez 和 Gomez-Sanchez 1995；Nishimura 等人，1998）。此外，MNC 中存在改变 ENaC 表达的已知靶标——盐皮质激素受体 (MR)（Amin 等，2005）。这些发现表明中枢 ENaC 抑制可能是治疗心血管疾病的潜在新靶点（Teiwes 和 Toto 2007）。尽管有这些发现，ENaC 的功能意义及其在跨国公司中受 MR 的调节仍完全未知。因此，本研究项目的总体目标是表征 ENaC 在跨国公司中的功能意义。我们假设 ENaC 影响 VP 和 OT 神经元的放电模式，最终影响这些激素的分泌，并且这些神经元中 ENaC 的异常表达/调节至少部分地导致盐敏感个体中 VP 和/或 OT 的异常分泌。为了解决这一假设，我们将采用全细胞膜片钳技术结合单细胞 RT-PCR 和免疫细胞化学来确定：1）VP 和 OT 神经元中 ENaC 介导的电流的存在和电生理特征； 2)在盐敏感大鼠的动物模型中是否观察到VP和OT神经元中ENaCs的异常表达/调节。 公共卫生相关性 上皮钠通道存在于肾脏中，在人类高血压的发展中发挥着重要作用，在下丘脑的脑加压素 (VP) 和催产素 (OT) 神经元的心血管调节中心中也发现了上皮钠通道。虽然大脑 ENaC 可能是治疗心血管疾病的潜在新靶点，但 ENaC 在 VP 和 OT 神经元中的功能意义尚不清楚。本提案中的研究将阐明这一关键机制，并将提高我们控制高血压的能力。