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 有必要转变为独立资助的调查员，领导专注于性的研究项目 心血管和肾脏生理学的差异。高血压、肾脏相关疾病较多 与绝经前女性相比，男性和绝经后女性常见。肾脏嘌呤信号传导 已成为控制血压和钠稳态的重要系统。我们最近有一个 有证据表明雌二醇 (E2) 刺激 Na 排泄并增加肾脏嘌呤能受体的表达 (P2Y2&4-R)。重要的是，嘌呤能系统的性别差异已在非肾组织中得到证实， 然而，肾脏嘌呤信号传导的性别相关差异尚不清楚。新型雌激素受体 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 处理尚未定义。我们的初步数据表明，肾髓质中 GPER 的激活促进 雌性大鼠通过内皮素-1 (ET-1) 依赖性机制排泄 Na。在当前的提案中， 总体假设是，女性肾钠处理能力的增强至少部分归因于 ATP/P2Y2&4-R/ 肾髓质内磷脂酶 C/上皮 Na 通道 (ENaC) 和 E2/GPER/ET-1/ENaC 信号传导。 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具有增强能力 与男性相比，肾髓质中的 P2Y2&4-R 信号传导对高盐摄入的反应。第二个目标将 确定局部合成的E2是否激活肾髓质中的GPER以促进ET-1依赖性 雌性大鼠通过抑制 ENaC 实现尿钠排泄。在 David Pollock 博士和联合导师的指导下，Dr. Edward Inscho，Gohar 博士扩展了她目前对嘌呤能信号传导和快速雌激素信号传导的研究 并提出了涉及三个主要目标的额外培训：i) 技术开发；戈哈尔博士将 发展钙成像、RNA 测序等领域的知识和技术专长 生物信息学，除了提高她的手术技能之外，ii) 实验室管理方面的专业职业发展， 指导和资助写作，iii) 转化研究培训。这个五年计划将为 Gohar 博士做好准备 R01 的提交使她走上了成功的独立职业生涯的道路。

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.