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1 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Department of Anatomy, University of Aarhus, Aarhus, Denmark
2 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Department of Physiology, Dongguk University, School of Medicine, Kyungju, MD, Korea, Republic of
3 The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; Institute of Experimental and Clinical Research, University of Aarhus, Aarhus, Denmark
4 Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: sn{at}ana.au.dk.
Lithium-induced nephrogenic diabetes insipidus (NDI) is associated with increased renal sodium excretion in addition to severe urinary concentrating defects. However, the molecular basis for the altered renal sodium excretion remains undefined. 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 protein abundance of 
ENaC and 
ENaC in the cortex and outer medulla. Moreover, immunocytochemistry 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 NaCl cotransporter NCC, the key renal sodium transporters upstream from the connecting tubule (including the 
1-subunit of Na,K-ATPase, NHE3 and NKCC2) 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 lithium-induced increase in fractional excretion of sodium.
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