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

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 (2014)

Publication Type: Journal article, Original article

Publication year: 2014

Journal

Original Authors: Buchholz B., Schley G., Faria D., Kroening S., Willam C., Schreiber R., Klanke B., Burzlaff N., Jantsch J., Kunzelmann K., Eckardt K.-U.

Publisher: American Society of Nephrology

Book Volume: 25

Pages Range: 465-474

Journal Issue: 3

DOI: 10.1681/ASN.2013030209

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.

Authors with CRIS profile

Involved external institutions

Universität Regensburg Germany (DE)

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://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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