Hypoxia-inducible factor-1? causes renal cyst expansion through calcium-activated chloride secretion.

ABSTRACT: Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in kidney function over time. We previously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1? (HIF-1?) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1?-target gene, glucose transporter 1, and report that HIF-1? 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-1? levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1? 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-1? by chetomin and knockdown of HIF-1? both decreased cyst growth in these models. Consistent with previous reports, plMDCK cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1? almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1?-dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth.

SUBMITTER: Buchholz B 

PROVIDER: S-EPMC3935579 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature