Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros.
Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros.
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DOI：
10.1016/j.ydbio.2013.01.017
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发表时间：
2013-04-01
影响因子：
2.7
通讯作者：
Wessely, Oliver
中科院分区：
文献类型：
--
作者：
Zhang, Bo;Romaker, Daniel;Ferrell, Nicholas;Wessely, Oliver
在肾脏中，近端小管对水、离子和有机溶质的再吸收非常重要。它们由高度特化的上皮细胞组成，其特征是精心设计的顶端刷状边界，以提高运输效率。利用非洲爪蟾的肾原，我们发现g蛋白调节剂霍乱毒素导致近端肾小管大小的急剧减少。这种表型伴随着细胞结构的改变，其特征是远端小管标记物4A6的异位表达和蛋黄血小板降解的损害。此外，霍乱毒素引起水肿形成。然而，这种表型不是由于肾脏缺陷，而是由于脉管系统发育受损。基于反义morpholino寡聚物以及药物激动剂和拮抗剂的实验，我们可以证明，霍乱毒素在肾病原肾中的复杂表型是由单个g蛋白α亚基gna的过度激活引起的。这反过来导致cAMP水平升高，触发rapgef4依赖的信号盒，并扰乱外吞和内吞作用。Ctx对分泌途径的干扰不仅在爪蟾胚胎中观察到。此外，在人近端小管细胞系中，霍乱毒素或rapgef4特异性激动剂增加了fitc标记白蛋白的摄取并减少了其分泌。基于这些数据，我们提出Gnas/cAMP/Rapgef4通路调节诱导近端小管增殖以获得最终器官大小的信号。
In the kidney, proximal tubules are very important for the reabsorption of water, ions and organic solutes from the primary urine. They are composed of highly specialized epithelial cells that are characterized by an elaborate apical brush border to increase transport efficiency. Using the pronephric kidney of Xenopus laevis we discovered that the G-protein modulator cholera toxin resulted in a dramatic reduction of the proximal tubular size. This phenotype was accompanied by changes in the cytoarchitecture characterized by ectopic expression of the distal tubular marker 4A6 and an impairment of yolk platelet degradation. In addition, cholera toxin caused edema formation. However, this phenotype was not due to kidney defects, but rather due to impaired vasculature development. Based on experiments with antisense morpholino oligomers as well as pharmacological agonists and antagonists, we could show that the complex phenotype of cholera toxin in the pronephric kidney was caused by the hyperactivation of a single G-protein alpha subunit, Gnas. This—in turn—caused elevated cAMP levels, triggered a Rapgef4-dependent signaling cassette and perturbed exo- and endocytosis. This perturbation of the secretory pathway by Ctx was not only observed in Xenopus embryos. Also, in a human proximal tubular cell line, cholera toxin or a Rapgef4-specific agonist increased uptake and decreased secretion of FITC-labeled Albumin. Based on these data we propose that the Gnas/cAMP/Rapgef4 pathway regulates the signals inducing the proliferation of proximal tubules to acquire their final organ size.
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