Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus
AuthorPoulsen, Søren Brandt
Kristensen, Tina Bøgelund
Brooks, Heddwen L.
Kohan, Donald E.
Fenton, Robert A.
AffiliationUniv Arizona, Coll Med, Dept Physiol
MetadataShow full item record
PublisherAMER SOC CLINICAL INVESTIGATION INC
CitationRole of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus 2017, 2 (7) JCI Insight
RightsCopyright © 2017, American Society for Clinical Investigation
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractPsychiatric 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. AC6loxloxCre 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.
NoteOpen Access Journal.
VersionFinal published version
SponsorsNovo Nordisk Foundation; Lundbeck Foundation; Danish Medical Research Council; National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK110621-01]; O'Brien Center for Acute Kidney Injury Research [P30DK079337]; Diabetes Endocrinology Research Center [P30DK063491]; American Heart Association [15BGIA22410018]; Satellite Healthcare