Abstract
Lithium is widely used in the treatment of bipolar affective disorders, but often causes nephrogenic diabetes insipidus (NDI), a condition characterized by a severe urinary concentrating defect. Lithium-induced NDI is associated with dysregulation of the amiloride-sensitive epithelial sodium channel (ENaC), which is essential for renal sodium reabsorption. Sex hormones have been shown to affect the expression of aquaporin-2 (AQP2) and sodium transporters. Therefore, we evaluated whether tamoxifen (TAM), a selective estrogen receptor modulator (SERM), would affect lithium-induced dysregulation of ENaC subunits and natriuresis. Rats were fed with lithium-containing food for 2 weeks to induce NDI and natriuresis. TAM was administered daily via gastric gavage after 1 week of lithium administration. Lithium treatment alone resulted in increased urinary sodium excretion and significant reduction of βENaC and γENaC at both RNA and protein levels. In addition, the plasma sodium level reduced after lithium treatment. Administration of TAM prevented increased urinary sodium excretion as well as attenuated the downregulation of βENaC and γENaC. Consistent with these findings, immunohistochemistry (IHC) showed stronger labeling of βENaC and γENaC subunits in the apical domain of the collecting duct cells in the cortical tissue of lithium-fed rats treated with TAM. Other major sodium transporters including NaPi-2, NKCC2, Na/K-ATPase, and NHE3, are believed not to have an effect on the increased urinary sodium excretion since their expression increased or was unchanged after treatment with lithium. In conclusion, the results demonstrated that TAM rescued the adverse effects of the lithium-induced increase in fractional excretion of sodium after the establishment of lithium-induced NDI.
Highlights
Lithium is an important drug, which is widely used in the management of bipolar disorders
Compatible with the distal effects of lithium, Kwon et al showed that several major renal sodium transporters, including the type 3 Na/H exchanger (NHE3), Na-K-ATPase, and Na-K-2Cl cotransporter (NKCC2) were not downregulated in response to lithium treatment, (Kwon et al, 2000) suggesting that these sodium transporters are not likely to be involved in the development of natriuresis after lithium administration
We showed that TAM rescued the adverse effects of lithiuminduced polyuria after the establishment of lithium-induced nephrogenic diabetes insipidus (NDI), and we want to investigate whether TAM plays a role the regulation of lithium-induced natriuresis after induction of lithium-NDI
Summary
Lithium is an important drug, which is widely used in the management of bipolar disorders. Previous studies identified marked downregulation of the ENaC subunits β and γ in the cortical and outer medullary (OM) collecting duct in lithiuminduced NDI (Nielsen et al, 2003). These changes, affecting the chief sites of sodium reabsorption in the collecting duct, indicate that this sodium channel is likely to play a role in lithiuminduced natriuresis (Nielsen et al, 2003). Strategies to prevent natriuresis in lithium-induced NDI have so far been unsuccessful; future studies will search for alternative drug targets for the treatment of this disease
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