Primary cilia and modulation of the renal microcirculation

原发纤毛和肾微循环的调节

• 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
• 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

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)：原发纤毛功能障碍与许多人类疾病和遗传性疾病有关，呈现出广泛的临床特征。致密黄斑细胞上已发现初级纤毛，但其在调节肾功能中的作用尚不清楚。致密黄斑通过检测氯化钠浓度的增加和促进腺苷或三磷酸腺苷的释放来调节小管球反馈(TGF)，从而收缩传入小动脉。然而，关于致密黄质纤毛在调节肾脏血流动力学、盐分和水分排泄方面的作用，人们知之甚少。我们的初步数据表明，在分离的灌流的肾小球旁装置(JGA)中，肾小管血流的升高增加了致密斑内细胞内钙浓度，激活了一氧化氮合酶1(NOS1)，并减弱了转化生长因子的反应。然而，致密黄斑上的纤毛作为启动这一反应的流量传感器的作用仍有待确定。正常情况下，向致密黄斑的钠供应增加会引起转化生长因子反应，并使传入小动脉收缩。然而，随着盐负荷的体积扩张，近端小管的钠重吸收受到抑制，导致流向致密斑区的流量持续上升。在这些条件下，我们认为初级纤毛受到刺激，细胞内钙离子增加，一氧化氮的形成增加，从而抑制和重置转化生长因子的反应。重置转化生长因子是防止肾小球滤过率(GFR)下降，使盐负荷快速排出的重要调节机制。我们进一步提出，致密黄斑纤毛或NOS1的缺失可阻止对转化生长因子反应性的流量调节，并通过阻止容量扩张后GFR的升高而损害盐负荷的排泄，从而促进盐敏感型高血压的发展。