title: AQP2-Induced Acceleration of Renal Cell Proliferation Involves the Activation of a Regulatory Volume Increase Mechanism Dependent on NHE2.
abstract: We have previously shown in renal cells that expression of the water channel Aquaporin 2 (AQP2) increases the rate of cell proliferation by shortening the transit time through the S and G2/M phases of the cell cycle. This acceleration is due, at least in part, to a down-regulation of regulatory volume decrease (RVD) mechanisms when volume needs to be increased in order to proceed into the S phase. We hypothesize that in order to increase cell volume, RVD mechanisms may be overtaken by regulatory volume increase mechanisms (RVI). In this study, we investigated if the isoform 2 of the Na+/H+exchanger (NHE2), the main ion transporter involved in RVI responses, contributed to the AQP2-increased renal cell proliferation. Three cortical collecting duct cell lines were used: WT-RCCD1(not expressing AQPs), AQP2-RCCD1(transfected with AQP2), and mpkCCDc14(with inducible AQP2 expression). We here demonstrate, for the first time, that both NHE2 protein activity and expression were increased in AQP2-expressing cells. NHE2 inhibition decreased cell proliferation and delayed cell cycle progression by slowing S and G2/M phases only if AQP2 was expressed. Finally, we observed that only in AQP2-expressing cells a NHE2-dependent RVI response was activated in the S phase. These observations suggest that the AQP2-increased proliferation involves the activation of a regulatory volume increase mechanism dependent on NHE2. Therefore, we propose that the accelerated proliferation of AQP2-expressing cells requires a coordinated modulation of the RVD/RVI activity that contributes to cell volume changes during cell cycle progression. J. Cell. Biochem. 118: 967-978, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Facultad de Medicina, Departamento de Ciencia Fisiológicas, Laboratorio de Biomembranas, IFIBIO Houssay, CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Valeria
authors.initials: V
authors.lastname: Rivarola
authors.affiliation: Facultad de Medicina, Departamento de Ciencia Fisiológicas, Laboratorio de Biomembranas, IFIBIO Houssay, CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Gisela
authors.initials: G
authors.lastname: Di Giusto
authors.affiliation: Facultad de Medicina, Departamento de Ciencia Fisiológicas, Laboratorio de Biomembranas, IFIBIO Houssay, CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: María José
authors.initials: MJ
authors.lastname: Christensen
authors.affiliation: Facultad de Medicina, Departamento de Ciencia Fisiológicas, Laboratorio de Biomembranas, IFIBIO Houssay, CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Paula
authors.initials: P
authors.lastname: Ford
authors.affiliation: Facultad de Medicina, Departamento de Ciencia Fisiológicas, Laboratorio de Biomembranas, IFIBIO Houssay, CONICET-UBA, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Capurro
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D048429:Cell Size; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D007672:Kidney Cortex / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism*
chemical_list: C496025:Aqp2 protein, rat; D051399:Aquaporin 2; C513110:Slc9a2 protein, rat; D017923:Sodium-Hydrogen Exchangers
keywords: AQUAPORIN 2; CELL PROLIFERATION; Na+/H+ EXCHANGER; REGULATORY VOLUME INCREASE