Tubuloglomerular feedback response in AKI to CKD transition

AKI 向 CKD 转变中的肾小球反馈反应

基本信息

批准号：
10533630
负责人：
RUISHENG LIU
金额：
$ 65.77万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-29 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10533630
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 Acute Renal Failure with Renal Papillary Necrosis Address Adenosine Adult African American population Blood Pressure Cells Chronic Kidney Failure Closure by clamp Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Elderly Excretory function Exhibits Feedback Generations Glomerular Filtration Rate Health High Prevalence Histology In Vitro Injury to Kidney Juxtaglomerular Apparatus Kidney Laboratories Macula densa Measurement Measures Mediating Microdissection Micropuncture Modeling Mus Nephrons Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Optics Outcome Pathway interactions Persons Phosphatidylinositols Play Prevention RNA Splicing Recovery Renal function Reperfusion Injury Risk Factors Role Sodium Survivors Techniques Testing Time Tubular formation Variant Waste Products adverse outcome arteriole base cost cytokine high risk in vivo laser capture microdissection mouse model new therapeutic target overexpression prevent renal ischemia response therapeutic target

项目摘要

Acute kidney injury (AKI) is associated with higher risk of developing chronic kidney disease (CKD), which is a growing health problem afflicting over 37 million US adults with cost over $80 billion every year. However, the underlying mechanisms, especially the risk factors that contribute to development into CKD for people with AKI has not been fully elucidated. Additionally , no specific therapy is available in prevention of AKI to CKD transition. Therefore, further understanding the pathophysiological mechanisms is essential for identification of new therapeutic targets for prevention of AKI to CKD transition. Decrease in GFR is a hallmark for AKI and CKD. TGF response is one of important mechanisms that regulate GFR. NOS1β is the primary splice variant and contributes to most of the NO generation by the macula densa. Recently, several studies from our laboratory demonstrated the decisive role of macula densa NOS1β-modulated TGF response in the long-term control of GFR, sodium excretion and blood pressure. However, whether the macula densa NOS1β-modulated TGF responsiveness plays a significant role in transition to CKD from AKI is unknown. In the present proposal, we propose to test our central hypothesis that following renal IRI, NOS1β expression and activity in the macula densa are decreased, which enhance TGF responsiveness and decrease GFR, thereby promoting transition to CKD. Rescue of macula densa NOS1 prevents AKI to CKD transition.

急性肾损伤（AKI）与患慢性肾病（CKD）的较高风险相关，日益严重的健康问题困扰着超过 3700 万美国成年人，每年造成的损失超过 800 亿美元。潜在机制，尤其是导致 AKI 患者发展为 CKD 的风险因素尚未完全阐明。，目前尚无特异性疗法可预防 AKI 向 CKD 的转变。因此，进一步了解其病理生理机制对于识别新的疾病至关重要。预防 AKI 向 CKD 转变的治疗目标。 GFR 降低是 AKI 的标志，而 TGF 反应是调节的重要机制之一。 GFR。NOS1β 是主要的剪接变体，有助于致密斑产生大部分 NO。最近，我们实验室的多项研究证明了NOS1β调节的致密黄斑的决定性作用然而TGF在长期控制GFR、钠排泄和血压方面的反应是否有效。致密斑 NOS1β 调节的 TGF 反应在 AKI 向 CKD 的转变中发挥重要作用未知。在本提案中，我们建议检验我们的中心假设，即肾脏 IRI 后，NOS1β 表达致密斑的活性降低，从而增强 TGF 反应性并降低 GFR，促进向 CKD 的转变，从而阻止 AKI 向 CKD 的转变。