期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：11
页码：6428-6433
DOI：10.1073/pnas.1130871100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Hypertonicity induced by NaCl, but not by urea or mannitol, up-regulates expression of the {gamma} subunit of Na/K-ATPase in cells of the murine inner medullary collecting duct line (IMCD3) by activation of the Jun kinase 2 (JNK2) pathways. We examined the ionic mediators of the osmosensitive response. An increase in osmolality to 550 milliosmoles per kg of water (mosmol/kgH2O) for 48 h by replacement of NaCl with choline chloride did not prevent the up-regulation of the {gamma} subunit. Neither Na+ ionophores nor inhibitors of cellular Na+ uptake altered the up-regulation of the {gamma} subunit or JNK activation. Changes in cell cation concentrations driven by incubation in low-K+ medium were effective in up-regulating the 1 subunit of Na/K-ATPase but did not have any effect on the {gamma} subunit. The replacement of NaCl with choline chloride did not down-regulate {gamma}-subunit expression in cells adapted to hypertonicity. In contrast, the replacement of NaCl with sodium acetate, or pretreatment of cells with the Cl- channel inhibitor 5-nitro-2-(3-phenylpropyl-amino)benzoic acid (NPPB) completely blocked {gamma}-subunit up-regulation, inhibited JNK activation, and caused a significant decrement in cell survival in hypertonic but not isotonic conditions. In adapted cells, replacement of 300 mosmol/kgH2O NaCl with sodium acetate resulted in down-regulation of the {gamma} subunit. In conclusion, we describe a Na+-independent, Cl--dependent mechanism for hypertonicity-mediated activation of the JNK and the subsequent synthesis of the {gamma} subunit of Na/K-ATPase, which are necessary for cellular survival in these anisotonic conditions.
