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1The Water and Salt Research Center, University of Aarhus, DK-8000 Aarhus C, Denmark; 2Department of Physiology, School of Medicine, Dongguk University, Kyungju 780-714, Korea; and 3Laboratory of Kidney and Electrolyte Metabolism, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892
Submitted 24 March 2003 ; accepted in final form 13 August 2003
Lithium-induced nephrogenic diabetes insipidus is associated with increased renal sodium excretion in addition to severe urinary concentrating defects. However, the molecular basis for this altered renal sodium excretion remains undefined. The amiloride-sensitive sodium channel (ENaC) is expressed in the renal connecting tubule and collecting duct and is essential in renal regulation of body sodium balance and blood pressure. We hypothesized that dysregulation of ENaC subunits may be responsible for the increased sodium excretion associated with lithium treatment. Lithium treatment for 28 days resulted in severe polyuria, increased fractional excretion of sodium, and increased plasma aldosterone concentration. Immunoblotting revealed that lithium treatment induced a marked decrease in the protein abundance of 
-ENaC and 
-ENaC in the cortex and outer medulla. Moreover, immunohistochemistry and laser confocal microscopy demonstrated an almost complete absence of -ENaC and -ENaC labeling in cortical and outer medullary collecting duct, which was not affected by dietary sodium intake. In contrast, immunohistochemistry showed increased apical labeling of all ENaC subunits in the connecting tubule and inner medullary collecting duct in rats on a fixed sodium intake but not in rats with free access to sodium. Except for a modest downregulation of the thiazide-sensitive Na-Cl cotransporter, the key renal sodium transporters upstream from the connecting tubule (including the 
1-subunit of Na-K-ATPase, type 3 Na/H exchanger, and Na-K-2Cl cotransporter) were unchanged. These results identify a marked and highly segment-specific downregulation of -ENaC and -ENaC in the cortical and outer medullary collecting duct, chief sites for collecting duct sodium reabsorption, in rats with a lithium-induced increase in fractional excretion of sodium.
aldosterone; collecting duct; epithelial sodium channel; hypertension; nephrogenic diabetes insipidus; sodium reabsorption; sodium wasting
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