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.