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

Publikation: Forskning - peer reviewTidsskriftartikel

DOI

  • Søren Brandt Poulsen
  • Tina Bøgelund Kristensen
  • Heddwen L Brooks
    Heddwen L BrooksDepartment of Physiology, College of Medicine, University of Arizona, Tucson, Arizona, USA.
  • Donald E Kohan
    Donald E KohanDivision of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
  • Timo Rieg
    Timo RiegVA 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.

OriginalsprogEngelsk
TidsskriftSAP Insight
Vol/bind2
Tidsskriftsnummer7
Sider (fra-til)e91042
DOI
StatusUdgivet - 6 apr. 2017
Eksternt udgivetJa

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