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

Søren Brandt Poulsen, Tina Bøgelund Kristensen, Heddwen L Brooks, Donald E. Kohan, Timo Rieg, Robert A. Fenton

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)e91042
JournalJCI insight
Volume2
Issue number7
DOIs
StatePublished - Apr 6 2017

Fingerprint

Nephrogenic Diabetes Insipidus
Lithium
Aquaporin 2
Knockout Mice
Osmolar Concentration
Drinking
Collecting Kidney Tubules
Urine
Proton-Translocating ATPases
Proliferating Cell Nuclear Antigen
Adenylyl Cyclases
Psychiatry
adenylyl cyclase 6
Membranes

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Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus. / Poulsen, Søren Brandt; Kristensen, Tina Bøgelund; Brooks, Heddwen L; Kohan, Donald E.; Rieg, Timo; Fenton, Robert A.

In: JCI insight, Vol. 2, No. 7, 06.04.2017, p. e91042.

Research output: Contribution to journalArticle

Poulsen, Søren Brandt ; Kristensen, Tina Bøgelund ; Brooks, Heddwen L ; Kohan, Donald E. ; Rieg, Timo ; Fenton, Robert A. / Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus. In: JCI insight. 2017 ; Vol. 2, No. 7. pp. e91042.
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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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