title: Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus.
abstract: Psychiatric patients treated with lithium (Li+) may develop nephrogenic diabetes insipidus (NDI). Although the etiology of Li+-induced NDI (Li-NDI) is poorly understood, it occurs partially due to reduced aquaporin-2 (AQP2) expression in the kidney collecting ducts. A mechanism postulated for this is that Li+inhibits adenylyl cyclase (AC) activity, leading to decreased cAMP, reduced AQP2 abundance, and less membrane targeting. We hypothesized that Li-NDI would not develop in mice lacking AC6. Whole-body AC6 knockout (AC6-/-) mice and potentially novel connecting tubule/principal cell-specific AC6 knockout (AC6loxloxCre) mice had approximately 50% lower urine osmolality and doubled water intake under baseline conditions compared with controls. Dietary Li+administration increased water intake and reduced urine osmolality in control, AC6-/-, and AC6loxloxCremice. Consistent with AC6-/-mice, medullary AQP2 and pS256-AQP2 abundances were lower in AC6loxloxCremice compared with controls under standard conditions, and levels were further reduced after Li+administration. AC6loxloxCreand control mice had a similar increase in the numbers of proliferating cell nuclear antigen-positive cells in response to Li+. However, AC6loxloxCremice had a higher number of H+-ATPase B1 subunit-positive cells under standard conditions and after Li+administration. Collectively, AC6 has a minor role in Li-NDI development but may be important for determining the intercalated cell-to-principal cell ratio.
authors.affiliation: InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Søren Brandt
authors.initials: SB
authors.lastname: Poulsen
authors.affiliation: InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Tina Bøgelund
authors.initials: TB
authors.lastname: Kristensen
authors.affiliation: Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Heddwen L
authors.initials: HL
authors.lastname: Brooks
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.affiliation: VA San Diego Healthcare System, San Diego, California, USA.|Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
authors.affiliation: InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000201:enzymology*; D004195:Disease Models, Animal; D005260:Female; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D008094:Lithium / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D008094:Lithium; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6