Primary cilia and modulation of the renal microcirculation

原发纤毛和肾微循环的调节

• 批准号: 8895614
• 负责人: RUISHENG LIU
• 金额: $ 19.52万
• 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/8895614
• 关键词: Acute; Address; Adenosine; Animals; Attenuated; Blood Pressure; Calcium; Cells; Chronic; Cilia; Clinical; Conscious; Data; Development; Diet; 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; 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浓度的增加并促进腺苷或ATP的释放来介导小管肾小球反馈（TGF），腺苷或ATP的释放收缩传入小动脉。然而，很少有人知道的作用，纤毛在macla densa在调节肾脏血流动力学，盐和水的排泄。我们的初步数据表明，在孤立的灌注肾小球体（JGA）制剂中的小管流的升高增加致密斑细胞内钙浓度，激活一氧化氮合酶1（NOS 1）和减弱TGF反应。然而，作为启动这种反应的流量传感器的致密斑上的纤毛的作用仍有待确定。正常情况下，向致密斑的钠递送的增加诱导TGF反应并收缩传入小动脉。然而，在响应于盐负荷的体积膨胀之后，近端小管中的钠重吸收被抑制，导致流向致密斑的流量持续升高。在这些条件下，我们提出，初级纤毛被刺激，提高细胞内钙离子和增强抑制和重置TGF反应的一氧化氮的形成。TGF的重置是一种重要的调节机制，通过防止肾小球滤过率（GFR）下降来允许盐负荷的快速排泄。我们进一步提出，删除致密斑的纤毛或NOS 1阻止TGF反应性的流动调节，并通过阻止体积扩张后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。