RRC ID 30695
Author Zhang B, Romaker D, Ferrell N, Wessely O.
Title Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros.
Journal Dev Biol
Abstract 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.
Volume 376(1)
Pages 31-42
Published 2013-4-1
DOI 10.1016/j.ydbio.2013.01.017
PII S0012-1606(13)00035-3
PMID 23352791
PMC PMC3767149
MeSH Albumins Animals Cell Line Cholera Toxin / pharmacology Cyclic AMP / metabolism DNA Primers / genetics Fluorescein-5-isothiocyanate GTP-Binding Protein alpha Subunits, Gs / metabolism* GTP-Binding Proteins / metabolism* Guanine Nucleotide Exchange Factors / metabolism Histological Techniques Humans Immunohistochemistry In Situ Hybridization Kidney Tubules, Proximal / drug effects Kidney Tubules, Proximal / embryology* Kidney Tubules, Proximal / metabolism Microscopy, Electron, Transmission Pronephros / embryology* Pronephros / metabolism Pronephros / ultrastructure Signal Transduction / physiology* Xenopus laevis / embryology*
IF 2.896
Times Cited 5
DNA material X. laevis whole embryo(stage 25) EST clones XL099E15.