Understanding the physiology and pathophysiology of kidney-derived vasopressin

慢性肾脏疾病(CKD)影响着15%的美国成年人30，加压素是 与非糖尿病、糖尿病和多囊肾病(PKD)的进展有关。1-18 然而，后叶加压素加重肾脏进展的具体机制(S) 疾病目前还不清楚。加压素是一种由164个氨基酸组成的生物活性终末产物。 前肽和生理产物目前被认为仅限于大脑。我们 最近发现，在生理条件下，肾脏中也会产生加压素 在人和小鼠的PKD中表达增加。因此，这个项目的目的是 了解肾源性加压素的功能、调节和影响在健康和 疾病。我们有初步数据表明，缺乏肾脏来源的加压素的小鼠 远端肾单位改变了水的平衡。我们建议(1)确定机制 肾脏衍生的加压素通过其影响水平衡和(2)确定肾脏是否- 衍生的加压素参与了PKD的囊性生长和进展。成功完成 该项目将有助于澄清(S)地方和地方之间的相互作用机制 全身性加压素信号影响肾脏疾病，可能寻找新的治疗方法 CKD和PKD的目标和方法。工作将发生在最大和最多的 范德比尔特大学医学部内世界上科学多样的肾脏科 中心医学部。这个项目已经得到了广泛的外部支持(哈罗德 Amos医学院发展奖-2020)和以 财政支持和涉及内部和外部的全面职业发展计划 指导、研讨会和课程作业。

Chronic Kidney Disease (CKD) affects 15% of the US adult population30 and vasopressin is associated with progression of non-diabetic, diabetic, and polycystic kidney disease (PKD). 1-18 However, the specific mechanism(s) through which vasopressin worsens progression of kidney disease are unclear. Vasopressin is the biologically active end-product of a 164 amino acid pre- pro-peptide and physiologic production is currently thought to be limited to the brain. We recently found that vasopressin is also made in the kidney under physiologic conditions and expression is increased in PKD in both humans and mice. Therefore, the aim of this project is to understand the function, regulation, and impact of kidney-derived vasopressin in health and disease. We have preliminary data that show that mice that lack kidney-derived vasopressin in the distal nephron have altered water balance. We propose to (1) determine the mechanism through which kidney-derived vasopressin influences water balance and (2) determine if kidney- derived vasopressin is involved cyst growth and progression of PKD. Successful completion of this project will help clarify the mechanism(s) through which the interplay between local and systemic vasopressin signaling impacts kidney disease, potentially identifying new therapeutic targets and approaches for CKD and PKD. Work will occur in one of the largest and most scientifically diverse nephrology divisions in the world, within the Vanderbilt University Medical Center Department of Medicine. This project has already received extensive external (Harold Amos Medical Faculty Development Award – 2020) and institutional support in the form of financial support and a comprehensive career development plan involving internal and external mentorship, workshops, and coursework.