| Autor: |
Sassi A; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.; National Center of Competence in Research 'Kidney.ch,' Switzerland., Wang Y; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.; National Center of Competence in Research 'Kidney.ch,' Switzerland., Chassot A; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.; National Center of Competence in Research 'Kidney.ch,' Switzerland., Roth I; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland., Ramakrishnan S; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.; National Center of Competence in Research 'Kidney.ch,' Switzerland., Olivier V; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.; National Center of Competence in Research 'Kidney.ch,' Switzerland., Staub O; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland., Udwan K; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland., Feraille E; Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.; National Center of Competence in Research 'Kidney.ch,' Switzerland. |
| Abstrakt: |
Fine tuning of Na + reabsorption takes place along the aldosterone-sensitive distal nephron, which includes the collecting duct (CD), where it is mainly regulated by aldosterone. In the CD, Na + reabsorption is mediated by the epithelial Na + channel and Na + pump (Na + -K + -ATPase). Paracellular ion permeability is mainly dependent on tight junction permeability. Claudin-8 is one of the main tight junction proteins expressed along the aldosterone-sensitive distal nephron. We have previously shown a coupling between transcellular Na + reabsorption and paracellular Na + barrier. We hypothesized that aldosterone controls the expression levels of both transcellular Na + transporters and paracellular claudin-8 in a coordinated manner. Here, we show that aldosterone increased mRNA and protein levels as well as lateral membrane localization of claudin-8 in cultured CD principal cells. The increase in claudin-8 mRNA levels in response to aldosterone was prevented by preincubation with 17-hydroxyprogesterone, a mineralocorticoid receptor antagonist, and by inhibition of transcription with actinomycin D. We also showed that a low-salt diet, which stimulated aldosterone secretion, was associated with increased claudin-8 abundance in the mouse kidney. Reciprocally, mice subjected to a high-salt diet, which inhibits aldosterone secretion, or treated with spironolactone, a mineralocorticoid receptor antagonist, displayed decreased claudin-8 expression. Inhibition of glycogen synthase kinase-3, Lyn, and Abl signaling pathways prevented the effect of aldosterone on claudin-8 mRNA and protein abundance, suggesting that signaling of protein kinases plays a permissive role on the transcriptional activity of the mineralocorticoid receptor. This study shows that signaling via multiple protein kinases working in concert mediates aldosterone-induced claudin-8 expression in the CD. NEW & NOTEWORTHY In this study, we showed that aldosterone modulates claudin-8 expression in cultured collecting duct principal cells and in the mouse kidney. The upregulation of claudin-8 expression in response to aldosterone is dependent on at least glycogen synthase kinase-3, Lyn, and Abl signaling pathways, indicating the participation of multiple protein kinases to the effect of aldosterone. |
