Pax proteins have key roles in kidney development. Now, Gregory Dressler and colleagues report that Pax2 and Pax8 also function as regulators of salt and water homeostasis in adult kidneys.

“We previously proposed that Pax proteins recruit histone methyltransferases via the adaptor protein PAX-interacting protein 1 (PTIP) to imprint a renal epithelial cell fate,” explains Dressler. “Once this fate is established in the adult kidney, are Pax proteins still needed to maintain or regulate this fate? This is the essential question that our study was investigating.”

The researchers report that in adult mice, both Pax2 and Pax8 are expressed in the nuclei of the collecting ducts and the medulla, but only Pax8 is highly expressed in the proximal tubules. Adult mice with induced deletion of either Pax2 or Pax8 seemed to be healthy but those in which both genes were deleted showed severe polyuria and dehydration. Consistent with this phenotype, gene expression analysis and immunostaining of kidney sections indicated that solute carriers, including urea transporter 1 (UT1), UT2, aquaporin 2 (AQP2), AQP3 and AQP4, were significantly downregulated in the double-knockout mice.

Culture of mouse inner medullary collecting duct cells in high-salt conditions led to upregulation of Pax2 and Pax8 within 4–8 hours and of Uta1 and Uta3 mRNAs within 16 hours. Further studies showed that Pax8, but not Pax2, directly binds to the promoter region of Slc14a2, which encodes UT1 and UT2, and recruits the histone methyltransferase complex via PTIP, leading to upregulation of these transporters in response to high-salt conditions.

“I think our study has clinical relevance beyond the mechanistic aspects of urine concentration,” says Dressler. “Pax proteins are essential developmental regulators, yet we know little about their functions in adult tissues. Our results could apply to other Pax family members expressed in the nervous system, eyes, muscle or skeleton.”