HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease

Kraus A, Peters DJM, Klanke B, Weidemann A, Willam C, Schley G, Kunzelmann K, Eckardt KU, Buchholz B (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Kidney International Nature Publishing Group: Open Access Hybrid Model Option A

Book Volume: 94

Pages Range: 887-899

Journal Issue: 5

DOI: 10.1016/j.kint.2018.06.008

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1α in cyst-lining epithelial cells. To determine the relevance of HIF-1α for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1α co-deletion and HIF-1α stabilization using a prolyl-hydroxylase inhibitor. HIF-1α expression was enhanced in kidneys with progressive cyst growth induced by early Pkd1 deletion, but unchanged in the milder phenotype induced by later Pkd1 deletion. Hif-1α co-deletion significantly attenuated cyst growth in the severe, but not in the mild, phenotype. Application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype with rapid loss of renal function. HIF-1α expression was associated with induction of genes that mediate calcium-activated chloride secretion. Thus, HIF-1α does not seem to play a role in early cyst formation, but accelerates cyst growth during progressive polycystic kidney disease. This novel mechanism of cyst growth may qualify as a therapeutic target.

Authors with CRIS profile

Andre Kraus Department of Medicine 4 – Nephrology and Hypertension Alexander Weidemann Department of Medicine 4 – Nephrology and Hypertension Carsten Willam Department of Medicine 4 – Nephrology and Hypertension Gunnar Schley Department of Medicine 4 – Nephrology and Hypertension Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension Björn Buchholz Department of Medicine 4 – Nephrology and Hypertension

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

IZKF-J71 (M4): Inhibition of the purinergic receptor P2Y2R as a potential therapeutic intervention in ADPKD Jan. 1, 2019 - June 30, 2021

Involved external institutions

Universität Regensburg DE Germany (DE) Leiden University NL Netherlands (NL)

How to cite

APA:

Kraus, A., Peters, D.J.M., Klanke, B., Weidemann, A., Willam, C., Schley, G.,... Buchholz, B. (2018). HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease. Kidney International, 94(5), 887-899. https://doi.org/10.1016/j.kint.2018.06.008

MLA:

Kraus, Andre, et al. "HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease." Kidney International 94.5 (2018): 887-899.

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