Lithium-induced NDI in rats is associated with loss of alpha-ENaC regulation by aldosterone in CCD.

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 renal sodium wasting. The effect of 7-day aldosterone and spironolactone treatment on regulation of ENaC in rat kidney cortex was investigated in rats with 3 wk 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 with rats treated with lithium alone (1.11 +/- 0.05). Plasma lithium concentration was decreased by aldosterone (0.31 +/- 0.03 mmol/l) but unchanged with spironolactone (0.84 +/- 0.18 mmol/l) compared with rats treated with lithium alone (0.54 +/- 0.04 mmol/l). Immunoblotting showed increased protein expression of alpha-ENaC, the 70-kDa form of gamma-ENaC, and the Na-Cl cotransporter (NCC) in kidney cortex in aldosterone-treated rats, whereas spironolactone decreased alpha-ENaC and NCC compared with control rats treated with lithium alone. Immunohistochemistry confirmed increased expression of alpha-ENaC in the late distal convoluted tubule and connecting tubule and also revealed increased apical targeting of all three ENaC subunits (alpha, beta, and gamma) in aldosterone-treated rats compared with rats treated with lithium alone. Aldosterone did not, however, affect alpha-ENaC expression in the cortical collecting duct (CCD), which showed weak and dispersed labeling similar to that in rats treated with lithium alone. Spironolactone did not affect ENaC targeting compared with rats treated with lithium alone. This study shows a segment specific lack of aldosterone-mediated alpha-ENaC regulation in the CCD affecting both alpha-ENaC protein expression and trafficking, which may explain the increased sodium wasting associated with chronic lithium treatment.