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

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 (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.