Journal article
(Original article)


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


Publication Details
Author(s): Willam C, Eckhardt KU, Buchholz B, Schley G, Faria D, Kroening S, Willam C, Schreiber R, Klanke B, Burzlaff N, Jantsch J, Kunzelmann K, Eckardt KU
Publisher: American Society of Nephrology
Publication year: 2014
Volume: 25
Journal issue: 3
Pages range: 465-474
ISSN: 1046-6673

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. Copyright © 2014 by the American Society of Nephrology.



How to cite
APA: Willam, C., Eckhardt, K.-U., Buchholz, B., Schley, G., Faria, D., Kroening, S.,... Eckardt, K.-U. (2014). Hypoxia-inducible factor-1α causes renal cyst expansion through calcium-activated chloride secretion. Journal of the American Society of Nephrology, 25(3), 465-474. https://dx.doi.org/10.1681/ASN.2013030209

MLA: Willam, Carsten, et al. "Hypoxia-inducible factor-1α causes renal cyst expansion through calcium-activated chloride secretion." Journal of the American Society of Nephrology 25.3 (2014): 465-474.

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