GATA2 Regulates Body Water Homeostasis through Maintaining Aquaporin 2 Expression in Renal Collecting Ducts

The transcription factor GATA2 plays pivotal roles in early renal development, but its distribution and physiological functions in adult kidney are largely unknown. We examined the GATA2 expression pattern in the adult kidney by tracing green fluorescent protein (GFP) fluorescence inGata2 GFP/+ mice that recapitulate endogenous GATA2 expression and found a robust GFP expression specifically in the renal medulla. Upon purification of the GFP-positive cells, we found that collecting duct (CD)-specific markers, including aquaporin 2 (Aqp2), an important channel for water reabsorption from urine, were abundantly expressed. To address the physiological function of GATA2 in the CD cells, we generated renal tubular cell-specificGata2 -deficient mice (Gata2 -CKO) by crossingGata2 floxed mice with induciblePax8-Cre mice. We found that theGata2 -CKO mice showed a significant decrease inAqp2 expression. TheGata2 -CKO mice exhibited high 24-h urine volume and low urine osmolality, two important signs of diabetes insipidus. We introduced biotin-tagged GATA2 into a mouse CD-derived cell line and conducted chromatin pulldown assays, which revealed direct GATA2 binding to conserved GATA motifs in theAqp2 promoter region. A luciferase reporter assay using anAqp2 promoter-reporter showed that GATA2trans activatesAqp2 through the GATA motifs. These results demonstrate that GATA2 regulates theAqp2 gene expression in CD cells and contributes to the maintenance of the body water homeostasis.