Tamoxifen attenuates development of lithium-induced nephrogenic diabetes insipidus in rats

Abstract

Lithium is widely used in treatment of bipolar affective disorders but often causes nephrogenic diabetes insipidus (NDI), a disorder characterized by severe urinary-concentrating defects. Lithium-induced NDI is caused by lithium uptake by collecting duct principal cells and altered expression of aquaporin-2 (AQP2), which are essential for water reabsorption of tubular fluid in the collecting duct. Sex hormones have previously been shown to affect the regulation of AQP2, so we tested whether tamoxifen (TAM), a selective estrogen receptor modulator, would attenuate lithium-induced alterations on renal water homeostasis. Rats were treated for 14 days with lithium, and TAM treatment was initiated 1 wk after onset of lithium administration. Lithium treatment resulted in severe polyuria and reduced AQP2 expression, which were ameliorated by TAM. Consistent with this, TAM attenuated downregulation of AQP2 and increased phosphorylation of the cAMP-responsive element-binding protein, which induced AQP2 expression in freshly isolated inner-medullary collecting duct suspension prepared from lithium-treated rats. In conclusion, TAM attenuated polyuria dose dependently and impaired urine concentration and downregulation of AQP2 protein expression in rats with lithium-induced NDI. These findings suggest that TAM is likely to be a novel therapeutic option for lithium-induced NDI.

Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus

“…Our study showed that TAM treatment was associated with reduced blood lithium levels; hence, we cannot exclude the probability of an interaction between TAM and lithium, which resulted in the reduced blood lithium levels ( Tingskov et al, 2018 ). Since lithium-induced polyuria in animals correlated with plasma lithium levels ( Marples et al, 1995 ), we may postulate that urinary sodium excretion could also be affected by the plasma lithium levels.…”

“…TAM is a SERM, which exerts its effect via binding to either the membrane-bound ERGP receptor or one of the nuclear ER receptors (ERα or ERβ) ( Revankar et al, 2005 ; Catalano et al, 2014 ). We have recently demonstrated the expression of all three ER receptor subtypes in the kidney collecting ducts of rats with lithium-induced NDI ( Tingskov et al, 2018 ). TAM can have either anti-estrogenic or estrogenic effects, depending on the type of tissues and cells ( Lonard and Smith, 2002 ), and estrogen could induce renal tubular sodium reabsorption ( Brunette and Leclerc, 2001 ).…”

“…For lithium therapy, lithium chloride (Sigma-Aldrich, Copenhagen, Denmark) was added to the chow to achieve a concentration of 40 mmol/kg dry food. Lithium-treated rats received food containing 40 mmol/kg for 14 days (LiCl; n = 10), affording therapeutic levels of lithium in the serum ( Tingskov et al, 2018 ). The rats used as controls were fed an unsupplemented standard food (Altromin, Lage, Germany) for 14 days (CTL; n = 8).…”

“…Animals were euthanized by cervical dislocation after the use of excess anestetics (Sevoflurane, Abbott Scandinavia, Sweden) according to institutional guidelines and approved protocols. These male rats have been used in our previous study and functional data after treatment with lithium and TAM have been published ( Tingskov et al, 2018 ).…”

“…Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) that has an anti-estrogenic effect on the mammary glands and exhibits estrogenic effects on the cardiovascular and skeletal systems ( Lonard and Smith, 2002 ; Kim et al, 2014 ). Importantly, we have recently demonstrated that TAM is able to attenuate the downregulation of AQP2 in rats with lithium-induced NDI ( Tingskov et al, 2018 ). We showed that TAM rescued the adverse effects of lithium-induced polyuria after the establishment of lithium-induced NDI, and we now want to investigate whether TAM also plays a role the regulation of lithium-induced natriuresis after induction of lithium-NDI.…”