P2Y2R and Cyst Growth in Polycystic Kidney Disease.

Abstract

Polycystic kidney disease (PKD) is characterized by continuous cyst growth, which results in a decline in kidney function. Deletion of P2Y2R and pharmacological antagonism of purinergic signaling significantly reduced cyst growth in an orthologous PKD mouse model. P2Y2R was expressed in cysts of human PKD nephrectomies, which makes P2Y2R a reasonable target for treatment of PKD. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple bilateral kidney cysts that gradually enlarge, resulting in a decline in kidney function. Cyst growth is significantly driven by ATP-dependent chloride secretion mediated by the ion channel TMEM16A. This pathway is further augmented in advanced stages of the disease by hypoxia and activation of hypoxia-inducible factor (HIF)-1<i>α</i>. The mechanisms by which ATP leads to activation of TMEM16A and how HIF-1<i>α</i> contributes to cyst growth <i>in vivo</i> have remained elusive. Mice with an inducible tubule-specific deletion of <i>Pkd1</i> were compared with mice with an additional codeletion of the purinergic receptor <i>P2y2r</i>. Furthermore, animals were challenged by pharmacological activation of HIF-1<i>α</i> and <i>Pkd1</i>-deficient mice were treated with suramin, an antagonist of purinergic signaling. In addition, expression of P2Y2R, TMEM16A, and HIF-1<i>α</i> was analyzed in nephrectomy samples from 27 patients with ADPKD. Genetic deletion of <i>P2y2r</i> significantly inhibited cyst growth <i>in vivo</i>. In addition, aggravation of the polycystic phenotype mediated by pharmacological activation of HIF-1<i>α</i> was reduced by deletion of <i>P2y2r</i>. Application of suramin to pharmacologically inhibit purinergic signaling also suppressed cyst enlargement <i>in vivo</i>. Analysis of kidney samples from 27 patients with ADPKD revealed significant expression of P2Y2R at the luminal site of the cyst-lining epithelium. P2Y2R was significantly expressed in human and mouse polycystic kidneys. Deletion and antagonism of P2Y2R reduced cyst enlargement in an ADPKD mouse model.