Understanding the physiology and pathophysiology of kidney-derived vasopressin

慢性肾脏疾病（CKD）影响15%的美国成年人口30， 与非糖尿病、糖尿病和多囊肾疾病（PKD）的进展相关。1-18 然而，加压素抑制肾损害进展的具体机制， 疾病不清楚。加压素是一种164个氨基酸前体的生物活性终产物， 目前认为前肽和生理产生仅限于脑。我们 最近发现，在生理条件下，加压素也在肾脏中产生， 在人和小鼠的PKD中表达增加。因此，本项目的目的是 了解肾源性加压素的功能，调节和健康的影响， 疾病我们有初步的数据表明，缺乏肾源性加压素的小鼠， 远端肾单位改变了水平衡我们建议（1）确定机制 肾源性加压素通过其影响水平衡和（2）确定肾- 衍生的加压素参与PKD的囊肿生长和进展。成功完成 这一项目将有助于澄清地方和地方政府之间相互作用的机制， 系统性血管加压素信号传导影响肾脏疾病，可能发现新的治疗方法 CKD和PKD的目标和方法。工作将发生在一个最大的和最 范德比尔特大学医学部内， 中心医学部。这个项目已经得到了广泛的外部（哈罗德 阿莫斯医学院发展奖- 2020年）和机构支持的形式， 财政支持和全面的职业发展计划，包括内部和外部的 指导、研讨会和课程。

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.