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Aldosterone Upregulates Tight Junction Expression of Claudin‐4, Decreasing Paracellular Na + Permeability in the Renal Cortical Collecting Duct
Author(s) -
Rajagopal Madhumitha,
Yu Alan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.666.10
Subject(s) - paracellular transport , aldosterone , claudin , sgk1 , reabsorption , endocrinology , mineralocorticoid receptor , medicine , tight junction , chemistry , transcellular , mineralocorticoid , renal physiology , permeability (electromagnetism) , kidney , biology , glucocorticoid , biochemistry , membrane
Under conditions of low dietary salt intake, plasma aldosterone levels are upregulated, increasing Na + reabsorption in the renal cortical collecting duct (CCD). While aldosterone is known to enhance transcellular Na + reabsorption, its effect on paracellular transport remains unknown. Paracellular transport is mediated by tight junction (TJ) proteins called claudins. We used a murine CCD cell line, mpKCCD c14, to study the effect of aldosterone on paracellular transport. We found that aldosterone significantly increased transepithelial resistance (TER) and decreased paracellular Na + permeability (P Na ), when transcellular transport is blocked. We also found that aldosterone increased TJ expression of a Na + barrier claudin, claudin‐4, suggesting that increased claudin‐4 expression at the TJ is responsible for the decrease in P Na . To confirm this, we stably knocked–down claudin‐4 expression using shRNAs. This diminished both baseline TER and aldosterone‐induced increases in TER, and P Cl /P Na . Aldosterone is known to signal via a mineralocorticoid receptor and activate a serum glucocorticoid kinase (Sgk1) to enhance ENaC activity. We found that aldosterone induced changes in claudin‐4 expression and TER were also suppressed by treatment with RU486 (a steroid receptor blocker) and GSK650394 (aSgk1 antagonist). In summary, our data strongly suggests that aldosterone acts via a Sgk1 mediated pathway to upregulate expression of claudin‐4 at the TJ in the renal CCD, decreasing P Na , preventing back‐leak of actively reabsorbed Na + , and increasing net salt reabsorption. Consistent with our in‐vitro data, we have also shown that in mice fed a low salt diet renal claudin‐4 expression is enhanced.