Aquaporin-2 Promoter Is Synergistically Regulated by Nitric Oxide and Nuclear Factor of Activated T Cells

Background/Aims: We have previously shown that aquaporin-2 (AQP2) is down-regulated in the renal medulla of rats made hypertensive by chronic inhibition of nitric oxide synthase. It has been shown that AQP2 expression is regulated by the calcineurin/nuclear factor of activated T cells (NFATc). Nitric oxide (NO) regulates the activity of NFATc via c-Jun-N-terminal kinase 2 (JNK2). Therefore, we hypothesized that increases in NO enhance NFATc-mediated up-regulation of AQP2 promoter activity. Methods: AQP2 mRNA and protein expression were detected in mouse renal papilla. AQP2 promoter luciferase reporter-and NFAT luciferase reporter-transfected MDCK cells were used to determine AQP2 promoter activity and NFATc activity, respectively. Cells were incubated with classic activators and inhibitors of NFATc and the NO pathway. Results: Our results demonstrate that both Ca2+ and NO have a synergistic effect resulting in an increase in AQP2 mRNA and protein in mouse papilla and activation of the AQP2 promoter in kidney-derived cells. In addition, NO enhances Ca2+-induced NFATc activation. The underlying mechanism involves increased NFATc nuclear import and decreased export via protein kinase G-mediated inhibition of JNK1/2. Conclusions: This is the first study defining novel regulatory roles for NO and NFATc in the control of AQP2, which is an important renal protein. Copyright (C) 2011 S. Karger AG, Basel