Transcriptional regulatory factors of the Aqp2 gene.

Aquaporin-2 (AQP2), the water channel protein exclusively expressed in the kidney collecting duct, plays an essential role in water reabsorption and fluid homeostasis. Dysregulation of Aqp2 transcription and changes in protein abundance lead to water balance disorders such as nephrogenic diabetes insipidus or water overload states. Recent studies have revealed that Aqp2 transcription is highly selective, with only 35 of 3,659 genes exhibiting vasopressin-dependent regulation. Two enhancer elements within a CCCTC-binding factor-insulated topologically associating domain containing the Aqp2 gene control this precise regulation. Contrary to earlier assumptions, ChIP-seq analyses have demonstrated that cyclic adenosine monophosphate-responsive element binding protein (CREB) does not bind within 390 kb of the Aqp2 gene body. Instead, the extended transcription factor candidates, including GATA-binding protein 2 (GATA2), GATA3, and NFATc1, working cooperatively with Yes-associated protein (YAP), have been proposed as one of the key regulators of Aqp2 transcription. This review consolidates the current knowledge of Aqp2 gene regulation, focusing on recent transcriptional studies that have improved the understanding of AQP2 expression patterns. This review discusses the complexity of the Aqp2 gene regulation by integrating information from genome-wide analyses and mechanistic studies. Moreover, the findings provide important insights for translational research and represent significant progress in developing therapeutic strategies for water balance disorders.