Primary cilia and modulation of the renal microcirculation

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。在黄斑致密细胞上发现了初级纤毛，但其在肾脏功能调节中的作用尚不清楚。黄斑致密通过检测NaCl浓度的升高，促进腺苷或ATP的释放，收缩传入小动脉，介导小管肾小球反馈（TGF）。然而，关于纤毛在肾血流动力学、盐和水排泄中的调节作用，我们知之甚少。我们的初步数据表明，在离体灌注肾小球旁器（JGA）制剂中，管状血流的升高增加了黄斑致密细胞内钙浓度，激活了一氧化氮合酶1 (NOS1)，减弱了TGF的反应。然而，纤毛在密集黄斑上作为启动这种反应的流量传感器的作用仍有待确定。正常情况下，向黄斑致密区输送的钠增加可诱导TGF反应并收缩传入小动脉。然而，随着盐负荷引起的体积扩张，近端小管的钠重吸收受到抑制，导致流向黄斑致密的流量持续升高。在这些条件下，我们建议刺激初级纤毛，提高细胞内钙，促进一氧化氮的形成，抑制和重置TGF反应。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）的下降来允许盐负荷的快速排泄。我们进一步提出，黄斑致密的纤毛或NOS1的缺失阻止了TGF反应性的血流调节，并通过阻止GFR在体积扩张后的升高而损害了盐负荷的排泄，从而促进了盐敏感性高血压的发展。

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.