Sex Differences in Renal Sodium Handling

摘要 Eman Y.Gohar博士的K99/R00应用程序旨在获取知识和培训 有必要转变为一名独立资助的调查员，领导着眼于性的研究项目 心血管和肾脏生理学的差异。高血压和肾脏相关疾病更多 在男性和绝经后女性中常见，与绝经前女性相比。肾嘌呤能信号转导 已成为控制血压和钠动态平衡的重要系统。我们有一个最新的 雌二醇刺激钠排泄和增加肾脏嘌呤能受体表达的证据 (P2Y2和4-R)。重要的是，在非肾脏组织中已经证实了嘌呤能系统的性别差异， 然而，肾脏嘌呤能信号的性别差异尚不清楚。新的雌激素受体G 蛋白偶联雌激素受体(GPER)在肾髓质中表达。GPER激活引发 对盐引起的并发症的心血管和肾脏保护作用。然而，它在Na中的作用 尚未定义处理。我们的初步数据表明，肾髓质中GPER的激活促进了 雌性大鼠通过内皮素-1(ET-1)依赖机制排泄NA。在目前的提案中， 总体假设是，女性肾脏钠转运的增强至少部分是由于ATP/P2Y2和4-R/ 肾髓质内的磷脂酶C/上皮钠通道(ENaC)和E2/GPER/ET-1/ENaC信号通路。 这一假设将通过两个具体目标进行检验。其中一个目标是测试雌性老鼠是否增强了 肾髓质中的P2Y2&4-R信号与男性相比，对高盐摄入的反应。第二个目标是 确定局部合成的E2是否激活肾髓质GPER以促进ET-1依赖 抑制ENaC对雌性大鼠的利钠作用。在大卫·波洛克博士和共同导师的指导下， Gohar博士扩展了她目前对嘌呤能信号和快速雌激素信号的研究 并提出了涉及三个主要目标的额外培训：i)技术开发；Gohar博士将 发展钙成像、RNA测序和 生物信息学，除了磨练她的外科技能，ii)实验室管理方面的职业发展， 指导和资助写作，iii)翻译研究培训。这一五年计划将使戈哈尔博士为 R01提交，并让她走上了一条成功的独立职业生涯之路。

SUMMARY This K99/R00 application from Eman Y. Gohar, PhD, is designed to acquire the knowledge and training necessary to transition into an independently-funded investigator leading a research program focused on sex differences in cardiovascular and renal physiology. Hypertension and kidney-related diseases are more common in men and postmenopausal women compared to premenopausal women. Renal purinergic signaling has emerged as an important system in the control of blood pressure and Na+ homeostasis. We have a recent evidence that estradiol (E2) stimulates Na+ excretion and increases the expression of renal purinergic receptors (P2Y2&4-R). Importantly, sex differences in the purinergic system has been demonstrated in non-renal tissues, however sex-related differences in renal purinergic signaling are not clear. The novel estrogen receptor, G protein-coupled estrogen receptor (GPER), is expressed in the renal medulla. GPER activation elicits cardiovascular and nephroprotective effects against salt-induced complications. However, its role in Na+ handling is not yet defined. Our preliminary data indicate that activation of GPER in the renal medulla promotes Na+ excretion via an endothelin-1 (ET-1)-dependent mechanism in female rats. In the current proposal, the overall hypothesis is that the enhanced renal Na+ handling in females is due, at least in part, to ATP/P2Y2&4-R/ phospholipase C/ epithelial Na+ channels (ENaC) and E2/GPER/ET-1/ENaC signaling within the renal medulla. This hypothesis will be tested by two specific aims. One aim will test whether female rats have enhanced P2Y2&4-R signaling in the renal medulla compared to males in response to high salt intake. The second aim will determine whether locally synthetized E2 activates GPER in the renal medulla to promote ET-1-dependent natriuresis in female rats via inhibition of ENaC. Under the mentorship of Dr. David Pollock and co-mentor, Dr. Edward Inscho, Dr. Gohar extends her current research on purinergic signaling and rapid estrogen signaling and proposes additional training that involves three major goals: i) technical development; Dr. Gohar will develop knowledge and technical expertise in the fields of calcium imaging, RNA sequencing and bioinformatics, beside refining her surgical skills, ii) professional career development in lab management, mentoring and grant writing, iii) training in translational research. This 5-year plan will prepare Dr. Gohar for an R01 submission and set her on a path for a successful independent career.