Primary cilia and modulation of the renal microcirculation

原发纤毛和肾微循环的调节

基本信息

批准号：
9068089
负责人：
RUISHENG LIU
金额：
$ 24.39万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9068089
关键词：
Acute Address Adenosine Animals Attenuated Blood Pressure Calcium Cells Chronic Cilia Clinical Conscious Data Development Equilibrium Eukaryotic Cell Excretory function Feedback Functional disorder Generations Glomerular Filtration Rate Health Hereditary Disease Human Genetics Image Immunohistochemistry In Vitro Injury Juxtaglomerular Apparatus Kidney Knock-out Knockout Mice Limb structure Link Macula densa Mediating Microcirculation Micropuncture Modeling Mus Mutation Nitric Oxide Nitric Oxide Synthase Type I Polycystic Kidney Diseases Preparation RNA Splicing Regulation Renal Blood Flow Renal function Retinal Degeneration Role Sodium Sodium Chloride Surface Techniques Telemetry Testing Thick Time Tissues Transgenic Mice Tubular formation Variant Water arteriole blood pressure regulation brain malformation cell type ciliopathy clinically significant falls hemodynamics high salt diet human disease in vivo mouse model novel prevent response salt sensitive hypertension sensor

项目摘要

DESCRIPTION (provided by applicant): Primary cilia dysfunction has been linked to numerous human diseases and genetic disorders, which present with a wide range of clinical features. Primary cilia have been found on the macula densa cells, but its role in the regulation of kidney function is unclear. The macula densa mediates tubuloglomerular feedback (TGF) by detecting the increases in NaCl concentration and promoting the release of adenosine or ATP that constricts the afferent arteriole. However, little is known about the role of cilia in the macla densa in the regulation of renal hemodynamics, salt and water excretion. Our preliminary data indicate that elevations in tubular flow in the isolated perfused juxtaglomerular apparatus (JGA) preparations increase macula densa intracellular calcium concentration, activates nitric oxide synthase 1 (NOS1) and attenuates TGF response. However, the role of the cilia on the macula densa as the flow sensor initiating this response remains to be determined. Normally increases in sodium delivery to the macula densa induce TGF response and constrict the afferent arteriole. However, following volume expansion in response to salt loading, sodium reabsorption in the proximal tubule is inhibited resulting in sustained elevations in flow to the macula densa. Under these conditions we propose that the primary cilia are stimulated, raise intracellular calcium and enhance the formation of nitric oxide that inhibits and resets TGF response. The resetting of TGF is an essential modulatory mechanism to allow for the rapid excretion of a salt load by preventing a fall in glomerular filtration rate (GFR). We further propose that deletion of the cilia or NOS1 of the macula densa prevents flow modulation of TGF responsiveness and impairs the excretion of a salt load by preventing the rise in GFR following volume expansion, hence promotes the development of salt-sensitive hypertension.

描述（由申请人提供）：原发性纤毛功能障碍与许多人类疾病和遗传性疾病有关，这些疾病和遗传性疾病具有广泛的临床特征。在致密斑细胞上发现了初级纤毛，但其在肾功能调节中的作用尚不清楚。致密斑通过检测 NaCl 浓度的增加并促进收缩传入小动脉的腺苷或 ATP 的释放来介导肾小球反馈 (TGF)。然而，人们对致密斑中的纤毛在调节肾血流动力学、盐和水排泄中的作用知之甚少。我们的初步数据表明，分离的灌注肾小球旁装置 (JGA) 制剂中肾小管流量的升高会增加致密斑细胞内钙浓度，激活一氧化氮合酶 1 (NOS1) 并减弱 TGF 反应。然而，致密斑上的纤毛作为启动这种响应的流量传感器的作用仍有待确定。通常，增加向致密斑输送的钠会诱导 TGF 反应并收缩传入小动脉。然而，在盐负荷导致体积膨胀后，近端小管中的钠重吸收受到抑制，导致流向致密斑的流量持续升高。在这些条件下，我们建议初级纤毛受到刺激，增加细胞内钙并增强一氧化氮的形成，从而抑制和重置 TGF 反应。 TGF 的重置是一种重要的调节机制，可通过防止肾小球滤过率 (GFR) 下降来快速排泄盐负荷。我们进一步提出，删除致密斑的纤毛或NOS1可以防止TGF反应性的流量调节，并通过防止体积扩张后GFR的升高来损害盐负荷的排泄，从而促进盐敏感性高血压的发展。