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  • Title: Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus.
    Author: Poulsen SB, Kristensen TB, Brooks HL, Kohan DE, Rieg T, Fenton RA.
    Journal: JCI Insight; 2017 Apr 06; 2(7):e91042. PubMed ID: 28405619.
    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 AC6loxloxCre mice. Consistent with AC6-/- mice, medullary AQP2 and pS256-AQP2 abundances were lower in AC6loxloxCre mice compared with controls under standard conditions, and levels were further reduced after Li+ administration. AC6loxloxCre and control mice had a similar increase in the numbers of proliferating cell nuclear antigen-positive cells in response to Li+. However, AC6loxloxCre mice 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.
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