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ENaC regulation by aldosterone in CCD
1 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Institute of Anatomy, University of Aarhus, Aarhus, Denmark
2 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Korea, Republic of
3 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Institute of Clinical Medicine, University of Aarhus, Aarhus, Denmark
4 Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: sn{at}ana.au.dk.
Lithium-induced nephrogenic diabetes insipidus (Li-NDI) is associated with increased urinary sodium excretion and decreased responsiveness to aldosterone and vasopressin. Dysregulation of the epithelial sodium channel (ENaC) is thought to play an important role in the renal sodium wasting. The effect of 7 day aldosterone and spironolactone treatment on regulation of ENaC in rat kidney cortex was therefore investigated in rats with 3 weeks of Li-NDI. Aldosterone treatment of rats with Li-NDI decreased fractional excretion of sodium (0.83 ± 0.02) whereas spironolactone did not change fractional excretion of sodium (1.10 ± 0.11) compared to rats treated with lithium alone (1.11 ± 0.05). Plasma lithium concentration was decreased by aldosterone (0.31 ± 0.03 mmol/l) while unchanged with spironolactone (0.84 ± 0.18 mmol/l) when compared to rats treated with lithium alone (0.54 ± 0.04 mmol/l). Immunoblotting showed increased protein expression of 
ENaC, the 70kDa from of 
ENaC and NCC in the kidney cortex in aldosterone-treated rats while spironolactone decreased ENaC and NCC when compared to control rats treated with lithium alone. Immunohistochemistry confirmed increased expression of ENaC in the late DCT and CNT and also revealed increased apical targeting of all three ENaC subunits (,
and ) in aldosterone-treated rats compared to rats treated with lithium alone. Aldosterone did not, however, affect ENaC expression in the CCD which showed weak and dispersed labeling similar to rats treated with lithium alone. Spironolactone did not affect ENaC targeting compared to rats treated with lithium alone. This study shows a segment specific lack of aldosterone mediated ENaC regulation in the CCD affecting both ENaC protein expression and trafficking which may explain the increased sodium wasting associated with chronic lithium treatment.
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