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疾病有关，这些疾病具有广泛的临床特征。在黄斑丹森细胞上发现了原发性纤毛，但其在肾功能调节中的作用尚不清楚。黄斑densa通过检测NaCl浓度的增加并促进收缩传入动脉的腺苷或ATP的释放，从而介导肾小管粉的反馈（TGF）。然而，关于纤毛在Macla densa中的作用在肾脏血流动力学，盐和水排泄的调节中的作用知之甚少。我们的初步数据表明，孤立的灌注偶然肠胃腔（JGA）制剂中的管状流量升高会增加黄斑densa细胞内钙浓度，激活一氧化氮合酶1（NOS1）（NOS1）并减轻TGF响应。然而，纤毛在黄斑densa中的作用作为启动此反应的流动传感器的作用尚待确定。通常，向黄斑丹森钠递送的钠递增会诱导TGF反应并收缩传入小动脉。然而，在响应盐负荷的体积膨胀后，近端小管中的钠重吸收受到抑制，从而导致流向黄斑丹森的流量持续升高。在这些条件下，我们建议刺激原发性纤毛，增加细胞内钙，并增强一氧化氮的形成，从而抑制并重置TGF反应。 TGF的重置是一种必不可少的调节机制，可以通过防止肾小球过滤率（GFR）降低盐负荷的快速排泄。我们进一步提出，黄斑densa的纤毛或NOS1的缺失可以防止TGF反应性的流动调节，并通过防止GFR膨胀后的GFR增加而损害盐负荷的排泄，因此促进了盐敏感性高血压的发展。