Pressure Natriuresis and Renal Na+ Transporter Regulation in Males and Females: Impact of Diabetes with Hypertension

项目总结 慢性肾脏病(CKD)是指肾脏过滤多余液体的能力逐渐下降。 和我们血液中的废物。慢性肾脏病的主要危险因素是高血压和2型。 糖尿病(T2D)，占所有CKD病例的73%。此外，50%-75%的T2D 患者会患上高血压(HTN)。肾脏在血压调节中起着核心作用。 通过建立个体的血压设定值。绝经前妇女血压偏低 与年龄匹配的男性相比，他们的得分和心血管疾病(CVD)的发病率更低。这 “女性优势”在较温和的表型和较慢的疾病进展中也很明显 与男性相比，HTN、心血管疾病和糖尿病肾病(DKD)的发病率更高。解决这一问题的机制 女性优势仍然是我们对肾脏生理学理解的一个重要差距。整体而言 这项提案的目标是定义关键的肾脏内环境平衡机制中的性别二型性 使用急性和慢性HTN模型影响BP、DKD和CVD，以减少发病率和 改进治疗方法。 目标1：确定导致更大急性肾小管损伤的机制和肾小管位置 F与M SD大鼠的压力性钠尿反应。我将利用经典的外科手术程序 通过血管收缩来增加血压，以确定特定性别的生理反应和 Na+转运体沿肾单位的调节。这些实验将提供对 女性优势的形成机制。 目的2：明确肾小管对HTN(瘦子M和F)反应的性别二型性 ZSF1)和T2D+HTN(肥胖雄性和雌性早期DKD大鼠)。(2.1)经过严格审查和高度审查的 将使用糖尿病肾病的翻译大鼠模型来研究性二型性 DKD的进展包括Na+转运体的调节、液体和电解质的处理、肾脏损伤 标志物和代谢生物标志物。AIM的建成将提供亟需的图景 男性和女性对DKD进展的肾小管反应。 这项拟议研究的目标是确定女性的关键肾脏代偿机制，以 男性和女性急性高血压和糖尿病合并HTN的影响。总括而言，我们的目标是 将我们所了解的关于女性优势的知识应用于男性和绝经后的女性，以告知 减少发病率和减缓疾病进展的治疗。

PROJECT SUMMARY Chronic kidney disease (CKD) is the gradual decline in the kidneys capacity to filter excess fluid and waste from our blood. The main risk factors for CKD are high blood pressure (BP) and type 2 diabetes mellitus (T2D), which account for 73% of all CKD cases. Furthermore, 50-75% of all T2D patients will develop hypertension (HTN). The kidneys play a central role in blood pressure regulation through establishment of an individual’s BP set point. Pre-menopausal women have lower BP set points and lower incidence of cardiovascular disease (CVD) compared to age-matched males. This “female advantage” is also evident in milder phenotypes and slower disease progression observed in HTN, CVD and diabetic kidney disease (DKD) compared to males. Mechanisms accounting for this female advantage remain an important gap in our understanding of renal physiology. The overall goals of this proposal are to define sexual dimorphisms in key renal homeostatic mechanisms that impact BP, DKD and CVD using acute and chronic models of HTN in order to reduce incidence and improve therapeutics. AIM 1: Determine mechanisms and tubular locations responsible for the greater acute pressure natriuresis response in F vs M SD rats. I will utilize classic surgical procedures to increase blood pressure by vascular constriction to define sex-specific physiological responses and Na+ transporter regulation along the nephron. These experiments will provide insights into the mechanisms of the female advantage. AIM 2: Define the sexual dimorphisms in the renal tubular responses to HTN (lean M and F ZSF1) and T2D+HTN (obese M and F ZSF1 rats with early DKD). (2.1) A well-vetted and highly translational rat model of diabetic kidney disease will be used to investigate the sexual dimorphisms in progression of DKD including Na+ transporter regulation, fluid and electrolyte handling, renal injury markers, and metabolic biomarkers. Completion of aim will provide much-needed picture of the tubular responses to DKD progression in both sexes. The goal of the proposed research is to define key renal compensatory mechanisms in females to acute hypertension and the impact of diabetes with HTN in males and females. Overall, we aim to apply what we learn about the female advantage to males and post-menopausal females to inform treatments to reduce incidence and slow disease progression.