Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

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  • Søren Brandt Poulsen
  • Tina Bøgelund Kristensen, Department of Biomedicine, Membranes Center & InterPrET Pilot Center, Health, Aarhus University, Aarhus, Denmark., Heddwen L Brooks, Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona, USA., Donald E Kohan, Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA., Timo Rieg, VA San Diego Healthcare System, San Diego, CA 92161, USA and Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA ,
  • Robert A Fenton

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 (AC6(loxloxCre)) 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 AC6(loxloxCre) mice. Consistent with AC6(-/-) mice, medullary AQP2 and pS256-AQP2 abundances were lower in AC6(loxloxCre) mice compared with controls under standard conditions, and levels were further reduced after Li(+) administration. AC6(loxloxCre) and control mice had a similar increase in the numbers of proliferating cell nuclear antigen-positive cells in response to Li(+). However, AC6(loxloxCre) 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.

TidsskriftJCI Insight
Sider (fra-til)e91042
StatusUdgivet - 6 apr. 2017

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