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: 7511111
• 负责人: RYOICHI TERUYAMA
• 金额: $ 20.88万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7511111
• 关键词: Address; Affect; Amiloride; Animal Model; Attenuated; Birth; Blood Circulation; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Defect; Development; Epithelial; Fire - disasters; 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; Public Health; 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; 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.

说明(申请人提供)：神经垂体激素加压素(VP)和催产素(OT)是位于下丘脑室旁核(PVN)和视上核(SON)内的大细胞神经元(MNC)合成的，并根据生理需要从神经垂体释放到全身循环中。VP的分泌在高渗透压、低血容量和低血压时增加，并产生抗利尿和升压作用(Sladek 2000)。除了众所周知的催产素在分娩和哺乳期间的作用外，血浆催产素在高钠血症时也会增加(Huang et al.，1995)，并导致钠尿(Conrad et al.，1986；Huang et al.，1994)。肾脏中存在非电压依赖性、阿米洛利敏感的上皮Na+通道(ENaCs)，并被认为有助于Na+和水的动态平衡(Benos等人，1995)。在人类中，大多数已知的高血压遗传原因是由于ENaC本身或其调节的缺陷，导致肾脏Na+重吸收异常增加(Dahlberg等人，2007；Lifton 1996；Mune等人，1995；Shimkets等人，1994；周等人，2007)。有趣的是，所有三个ENaC亚单位(1、2和3)的信使和蛋白质都已在大鼠大脑的心血管调节中心包括SON和PVN的MNC中得到证实(Amin等人，2005年)。脑室注射ENaC阻滞剂，阿米洛利类似物苯扎米，显著降低了盐依赖型高血压动物模型的高血压(Gomez-Sanchez和Gomez-Sanchez，1995；Nishimura等，1998)。此外，已知的ENaC表达改变的靶点是MNC中存在的盐皮质激素受体(MR)(Amin等人，2005年)。这些发现表明，中枢抑制ENaC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，但ENaCs的功能意义以及MRS对它们的调控在跨国公司中是完全未知的。因此，本研究的总体目标是研究ENaCs在跨国公司中的功能意义。我们推测，ENaCs影响VP和OT神经元的放电模式，最终影响这些激素的分泌，ENaCs在这些神经元中的异常表达/调节至少部分地导致盐敏感个体VP和/或OT的异常分泌。为了解决这一假设，我们将使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)ENaC介导的电流在VP和OT神经元中的存在及其电生理特征；2)在盐敏感大鼠的动物模型中是否观察到ENaC在VP和OT神经元中的异常表达/调节。与公共健康相关的上皮性钠通道存在于肾脏，在人类高血压的发生发展中起着重要作用，在下丘脑的脑血管加压素(VP)和催产素(OT)神经元的心血管调节中心也发现了这种通道。虽然脑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。这项建议的研究将阐明这一关键机制，并将提高我们管理高血压的能力。