title: Hypoxia-inducible factor-1α 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-1α (HIF-1α) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1α-target gene, glucose transporter 1, and report that HIF-1α 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-1α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1α 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-1α by chetomin and knockdown of HIF-1α 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-1α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1α-dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth.
authors.affiliation: Departments of Nephrology and Hypertension, and.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Buchholz
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.forename: Diana
authors.initials: D
authors.lastname: Faria
authors.forename: Sven
authors.initials: S
authors.lastname: Kroening
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.forename: Bernd
authors.initials: B
authors.lastname: Klanke
authors.forename: Nicolai
authors.initials: N
authors.lastname: Burzlaff
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jantsch
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000502:physiology*; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008810:Mice, Inbred C57BL; D007690:Polycystic Kidney Diseases / Q000209:etiology* / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D051246:Glucose Transport Proteins, Facilitative; D051795:Hypoxia-Inducible Factor 1, alpha Subunit