Hypoxia-Inducible Factor-1a Causes Renal Cyst Expansion through Calcium-Activated Chloride

Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and,through compressionof intactnephrons,leadtoadecline inkidneyfunctionovertime.Wepreviously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1a (HIF-1a) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1a–target gene, glucose transporter 1, and report that HIF-1a promotes renal cyst growth in two in vitro cyst models—principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse kidneys stimulated with forskolin. In both models, augmenting HIF-1a levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1a degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased cyst size in the embryonic kidney cyst model. In contrast, inhibition of HIF-1a by chetomin and knockdown of HIF-1a both decreased cystgrowthinthesemodels.Consistentwithpreviousreports,plMDCKcystenlargementwasdrivenlargelyby transepithelialchloridesecretion,whichconsists,inpart,ofacalcium-activatedchlorideconductance.plMDCKs deficient for HIF-1a almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1a–dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth.