Sex Differences in Renal Sodium Handling

总结 Eman Y. Gohar博士旨在获得知识和培训 有必要过渡到一个独立资助的调查员领导的研究计划，重点是性 心血管和肾脏生理学的差异。高血压和肾脏相关疾病较多 常见于男性和绝经后女性，与绝经前女性相比。肾嘌呤能信号 已经成为控制血压和Na+稳态的重要系统。我们最近有一个 雌二醇（E2）刺激Na+排泄并增加肾嘌呤能受体表达的证据 (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，肾嘌呤能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激活抑制剂 对盐引起的并发症具有心血管和肾保护作用。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的激活促进了 雌性大鼠通过内皮素-1（ET-1）依赖性机制的Na+排泄。在目前的提案中， 总的假设是，女性肾脏Na+处理能力的增强至少部分是由于ATP/P2Y2&4-R/ATP/P2Y2&4-R。 磷脂酶C/上皮Na+通道（ENaC）和肾髓质内的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。一个目标是测试雌性大鼠是否增强了 与男性相比，肾髓质中的P2Y2&4-R信号传导响应于高盐摄入。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的尿钠排泄。在大卫波洛克博士和共同导师的指导下， Edward Inscho博士，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 并提出了额外的培训，涉及三个主要目标：i）技术开发; Gohar博士将 发展钙成像，RNA测序和 生物信息学，除了提高她的手术技能，ii）实验室管理的专业职业发展， 指导和赠款写作，三）翻译研究培训。这个五年计划将为Gohar博士做好准备， R 01提交，并设置了一个成功的独立职业生涯的道路上她。

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.