Abstract
Lithium-induced nephrogenic diabetes insipidus (NDI) is accompanied by polyuria, downregulation of aquaporin 2 (AQP2), and cellular remodeling of the collecting duct (CD). The amiloride-sensitive epithelial sodium channel (ENaC) is a likely candidate for lithium entry. Here, we subjected transgenic mice lacking αENaC specifically in the CD (knockout [KO] mice) and littermate controls to chronic lithium treatment. In contrast to control mice, KO mice did not markedly increase their water intake. Furthermore, KO mice did not demonstrate the polyuria and reduction in urine osmolality induced by lithium treatment in the control mice. Lithium treatment reduced AQP2 protein levels in the cortex/outer medulla and inner medulla (IM) of control mice but only partially reduced AQP2 levels in the IM of KO mice. Furthermore, lithium induced expression of H+-ATPase in the IM of control mice but not KO mice. In conclusion, the absence of functional ENaC in the CD protects mice from lithium-induced NDI. These data support the hypothesis that ENaC-mediated lithium entry into the CD principal cells contributes to the pathogenesis of lithium-induced NDI.
Nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine in response to vasopressin. The disease is most commonly acquired and often occurs as an adverse effect in humans subjected to various drug treatments (e.g., lithium [Li] therapy). Li, which is a frequently used drug against manic-depressive illness, can cause NDI in up to 20 to 40% of patients who take the medication.1 Long-term Li treatment of rats results in severe downregulation of aquaporin 2 (AQP2) and AQP3 protein levels in parallel with extensive polyuria.2,3 Moreover, Li causes a remodeling of the rat kidney collecting duct (CD), which includes a decreased fraction of principal cells and an increased fraction of intercalated cells.4,5 These deleterious effects on the CD are proposed to be linked to Li accumulation within the principal cells. Several studies suggested that a likely candidate for Li entry is the epithelial sodium channel (ENaC), which is present in the late distal convoluted tubule (DCT) cells, the connecting tubule (CNT) cells, and the CD principal cells.6,7 ENaC is a heteromultimeric protein composed of three subunits: α, β, and γ.8 ENaC has a higher permeability for Li than for Na.9,10 Moreover, amiloride, a specific blocker of ENaC, has been shown to reduce Li uptake in ENaC-expressing renal cells11 and to block reabsorption in the distal nephron of Na-depleted rats.12 Recent studies also showed that amiloride partially prevents development of Li-NDI in rats11,13 and partially restores the urine-concentrating ability in patients who are on Li therapy.14 To provide possibly definitive proof of whether ENaC is involved in the absorption of Li, we took advantage of transgenic mice deficient of αENaC specifically in the CD while leaving ENaC expression in the late DCT and CNT intact.15 Under salt restriction, whole-cell voltage clamp of principal cells of the cortical CD (CCD) showed no detectable ENaC activity, whereas large amiloride-sensitive currents were observed in the CCD of controls15 and in the CNT/DCT of both KO and controls.16 Despite the loss of ENaC activity in CD, the animals survived well and were able to maintain Na and potassium (K) balance, even when challenged by 1 week of salt restriction, 23 hours of water deprivation, or 2 days of K loading.15 We followed these transgenic mice and their littermate controls during long-term Li treatment.
Christensen, B M