Cdc42 activation couples fluid shear stress to apical endocytosis in proximal tubule cells.
Cdc42 activation couples fluid shear stress to apical endocytosis in proximal tubule cells.
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DOI：
10.14814/phy2.13460
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发表时间：
2017-10
影响因子：
2.5
通讯作者：
Weisz OA
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Jean-Alphonse FG;Raghavan V;McGarvey JC;Rbaibi Y;Vilardaga JP;Carattino MD;Weisz OA
肾近端小管(PT)内的细胞对肾小球滤过率和伴随的流体剪切力(FSS)的急剧变化作出反应，以调节离子、葡萄糖和其他过滤分子的重吸收，并维持肾小球小管平衡。最近，我们发现PT细胞暴露于FSS也刺激顶端内吞能力的增加(Raghavan等人)。PNAS，111：8506-8511,2014)。我们发现，FSS引起细胞内钙离子浓度([Ca~(2+)]i)的增加，这需要细胞外ATP的释放和初级纤毛的存在。在这项研究中，我们阐明了FSS诱导的钙离子增加与心尖内皮细胞容量增加之间的关系。利用分子内FRET探针，我们证明了CDC42的激活在FSS刺激的心尖细胞吞噬级联反应中是必要的步骤。CDC42的激活需要初级纤毛和FSS介导的[Ca~(2+)]i升高。此外，CDC42的活性和FSS刺激的内吞作用受钙调蛋白激活剂和抑制剂的协调调节。综上所述，这些数据提示了PT细胞暴露于FSS的一种机制，通过这种机制，PT细胞对过滤分子的内吞摄取增加。
Cells lining the kidney proximal tubule (PT) respond to acute changes in glomerular filtration rate and the accompanying fluid shear stress (FSS) to regulate reabsorption of ions, glucose, and other filtered molecules and maintain glomerulotubular balance. Recently, we discovered that exposure of PT cells to FSS also stimulates an increase in apical endocytic capacity (Raghavan et al. PNAS, 111:8506–8511, 2014). We found that FSS triggered an increase in intracellular Ca2+ concentration ([Ca2+]i) that required release of extracellular ATP and the presence of primary cilia. In this study, we elucidate steps downstream of the increase in [Ca2+]i that link FSS‐induced calcium increase to increased apical endocytic capacity. Using an intramolecular FRET probe, we show that activation of Cdc42 is a necessary step in the FSS‐stimulated apical endocytosis cascade. Cdc42 activation requires the primary cilia and the FSS‐mediated increase in [Ca2+]i. Moreover, Cdc42 activity and FSS‐stimulated endocytosis are coordinately modulated by activators and inhibitors of calmodulin. Together, these data suggest a mechanism by which PT cell exposure to FSS is translated into enhanced endocytic uptake of filtered molecules.