alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus.
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.
Water and Salt Research Center, Department of Anatomy, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus C, Denmark. bmc@ana.au.dk
Birgitte Mønster
BM
Christensen
Annie Mercier
AM
Zuber
Johannes
J
Loffing
Jean-Christophe
JC
Stehle
Peter M T
PM
Deen
Bernard C
BC
Rossier
Edith
E
Hummler
D000042:Absorption; D000818:Animals; D051399:Aquaporin 2 / Q000032:analysis; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced*; D053503:Epithelial Sodium Channels / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000473:pathology; D018021:Lithium Chloride / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D006180:Proton-Translocating ATPases / Q000032:analysis
C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D053503:Epithelial Sodium Channels; C507047:Scnn1a protein, mouse; D006180:Proton-Translocating ATPases; D018021:Lithium Chloride