Pax2 and Pax8 Proteins Regulate Urea Transporters and Aquaporins to Control Urine Concentration in the Adult Kidney

Significance Statement Pax2 plays an essential role in kidney development, and although subsets of epithelial cells in the adult kidney continue to express Pax2 and the related Pax8 protein, their function in adult kidneys has not been defined. The authors examined phenotypes and altered gene expression patterns in adult mice lacking Pax2, Pax8, or both, showing that Pax2 and Pax8 regulate multiple transmembrane ion and water channels in the adult renal medulla, including aquaporins and urea transporters. Inner medullary collecting duct cells respond to high-salt levels by upregulating Pax8, leading to increased activation of such transporters through specific methylation of histones, defining a mechanism for regulating urine concentration. These findings point to a novel and redundant role for Pax proteins in regulating salt and water homeostasis in the adult kidney. Background As the glomerular filtrate passes through the nephron and into the renal medulla, electrolytes, water, and urea are reabsorbed through the concerted actions of solute carrier channels and aquaporins at various positions along the nephron and in the outer and inner medulla. Proliferating stem cells expressing the nuclear transcription factor Pax2 give rise to renal epithelial cells. Pax2 expression ends once the epithelial cells differentiate into mature proximal and distal tubules, whereas expression of the related Pax8 protein continues. The collecting tubules and renal medulla are derived from Pax2-positive ureteric bud epithelia that continue to express Pax2 and Pax8 in adult kidneys. Despite the crucial role of Pax2 in renal development, functions for Pax2 or Pax8 in adult renal epithelia have not been established. Methods To examine the roles of Pax2 and Pax8 in the adult mouse kidney, we deleted either Pax2, Pax8, or both genes in adult mice and examined the resulting phenotypes and changes in gene expression patterns. We also explored the mechanism of Pax8-mediated activation of potential target genes in inner medullary collecting duct cells. Results Mice with induced deletions of both Pax2 and Pax8 exhibit severe polyuria that can be attributed to significant changes in the expression of solute carriers, such as the urea transporters encoded by Slc14a2, as well as aquaporins within the inner and outer medulla. Furthermore, Pax8 expression is induced by high-salt levels in collecting duct cells and activates the Slc14a2 gene by recruiting a histone methyltransferase complex to the promoter. Conclusions These data reveal novel functions for Pax proteins in adult renal epithelia that are essential for retaining water and concentrating urine.