HIF ‐Regulated Pannexin‐1 Channel Drives Luminal ATP Accumulation in Kidney Cysts

Autosomal dominant polycystic kidney disease (ADPKD) is marked by the progressive development of bilateral kidney cysts, leading to compression of intact surrounding tissue and a subsequent decline in kidney function. Accumulation of ATP within the cyst fluid significantly drives cyst expansion by activating purinergic receptors, thereby promoting calcium-dependent chloride secretion. Moreover, the induction of hypoxia-inducible factor 1α (HIF-1α) in cyst-lining epithelial cells further enhances chloride conductance. However, the mechanisms underlying ATP release into the cyst fluid and the role of HIF-1α in cyst enlargement remain incompletely understood. Here, we demonstrate that the ATP-release channel Pannexin-1 is regulated by HIF-1α in kidney tubular cells, leading to its prominent localization at the apical membrane of kidney cysts in both human and murine ADPKD kidney tissue. Apical ATP release is elevated in PKD1-deficient cyst-forming cells following pharmacological induction of HIF-1α and attenuated by two Pannexin-1 inhibitors, Probenecid and Brilliant Blue FCF (BB-FCF). HIF-dependent cyst growth in vitro is inhibited by basolateral application of the cell-permeable Probenecid, whereas the cell-impermeable BB-FCF requires luminal application to exert its effect. In conclusion, HIF-1α promotes Pannexin-1 expression in cyst-lining cells, facilitating directional ATP release into the cyst lumen and driving ATP-dependent cyst expansion.