Ouabain Regulates CFTR-Mediated Anion Secretion and Na,K-ATPase Transport in ADPKD Cells

被引:13
作者
Jansson, Kyle [1 ,4 ]
Venugopal, Jessica [1 ,4 ]
Sanchez, Gladis [1 ,4 ]
Magenheimer, Brenda S. [2 ,4 ]
Reif, Gail A. [3 ,4 ]
Wallace, Darren P. [1 ,3 ,4 ]
Calvet, James P. [2 ,4 ]
Blanco, Gustavo [1 ,4 ]
机构
[1] Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, Kansas City, KS 66160 USA
[2] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS 66160 USA
[3] Univ Kansas, Med Ctr, Dept Med, Kansas City, KS 66160 USA
[4] Univ Kansas, Med Ctr, Kidney Inst, Kansas City, KS 66160 USA
基金
美国国家卫生研究院;
关键词
Polycystic kidney disease; Fluid secretion; Cystogenesis; Signaling; POLYCYSTIC KIDNEY-DISEASE; PLASMALEMMAL NA/K-ATPASE; FLUID SECRETION; CYSTIC-FIBROSIS; ENDOGENOUS OUABAIN; LLC-PK1; CELLS; K-ATPASE; GROWTH; PROLIFERATION; CHLORIDE;
D O I
10.1007/s00232-015-9832-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) requires the transepithelial secretion of fluid into the cyst lumen. We previously showed that physiological amounts of ouabain enhance cAMP-dependent fluid secretion and cyst growth of human ADPKD cyst epithelial cells in culture and formation of cyst-like dilations in metanephric kidneys from Pkd1 mutant mice. Here, we investigated the mechanisms by which ouabain promotes cAMP-dependent fluid secretion and cystogenesis. Ouabain (3 nM) enhanced cAMP-induced cyst-like dilations in embryonic kidneys from Pkd1 (m1Bei) mice, but had no effect on metanephroi from Pkd1 (m1Bei) mice that lack expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Similarly, ouabain stimulation of cAMP-induced fluid secretion and in vitro cyst growth of ADPKD cells were abrogated by CFTR inhibition, showing that CFTR is required for ouabain effects on ADPKD fluid secretion. Moreover, ouabain directly enhanced the cAMP-dependent Cl- efflux mediated by CFTR in ADPKD monolayers. Ouabain increased the trafficking of CFTR to the plasma membrane and up-regulated the expression of the CFTR activator PDZK1. Finally, ouabain decreased plasma membrane expression and activity of the Na,K-ATPase in ADPKD cells. Altogether, these results show that ouabain enhances net fluid secretion and cyst formation by activating apical anion secretion via CFTR and decreasing basolateral Na+ transport via Na,K-ATPase. These results provide new information on the mechanisms by which ouabain affects ADPKD cells and further highlight the importance of ouabain as a non-genomic stimulator of cystogenesis in ADPKD.
引用
收藏
页码:1145 / 1157
页数:13
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