HIF-Regulated Pannexin-1 Channel Drives Luminal ATP Accumulation in Kidney Cysts

Skoczynski K, Scholz JK, Ursu R, Schödel J, Grampp S, Naas S, Lauer V, Schiffer M, Büttner-Herold M, Buchholz B, Kraus A (2026)

Publication Type: Journal article

Publication year: 2026

Journal

The FASEB Journal Federation of American Society of Experimental Biology (FASEB)

Book Volume: 40

Article Number: e71892

Journal Issue: 10

DOI: 10.1096/fj.202502847RR

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is marked by the progressive development of bilateral kidney cysts, leading to compression of intact surrounding tissue and a subsequent decline in kidney function. Accumulation of ATP within the cyst fluid significantly drives cyst expansion by activating purinergic receptors, thereby promoting calcium-dependent chloride secretion. Moreover, the induction of hypoxia-inducible factor 1α (HIF-1α) in cyst-lining epithelial cells further enhances chloride conductance. However, the mechanisms underlying ATP release into the cyst fluid and the role of HIF-1α in cyst enlargement remain incompletely understood. Here, we demonstrate that the ATP-release channel Pannexin-1 is regulated by HIF-1α in kidney tubular cells, leading to its prominent localization at the apical membrane of kidney cysts in both human and murine ADPKD kidney tissue. Apical ATP release is elevated in PKD1-deficient cyst-forming cells following pharmacological induction of HIF-1α and attenuated by two Pannexin-1 inhibitors, Probenecid and Brilliant Blue FCF (BB-FCF). HIF-dependent cyst growth in vitro is inhibited by basolateral application of the cell-permeable Probenecid, whereas the cell-impermeable BB-FCF requires luminal application to exert its effect. In conclusion, HIF-1α promotes Pannexin-1 expression in cyst-lining cells, facilitating directional ATP release into the cyst lumen and driving ATP-dependent cyst expansion.

Authors with CRIS profile

Julia Scholz Department of Medicine 5 – Haematology and Oncology Raluca Ursu Department of Medicine 4 – Nephrology and Hypertension Johannes Schödel Department of Medicine 4 – Nephrology and Hypertension Steffen Grampp Department of Medicine 4 – Nephrology and Hypertension Stephanie Naas Department of Medicine 4 – Nephrology and Hypertension Victoria Lauer Department of Medicine 4 – Nephrology and Hypertension Mario Schiffer Lehrstuhl für Innere Medizin IV Maike Büttner-Herold Department of Nephropathology Andre Kraus Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Universität Regensburg DE Germany (DE)

How to cite

APA:

Skoczynski, K., Scholz, J.K., Ursu, R., Schödel, J., Grampp, S., Naas, S.,... Kraus, A. (2026). HIF-Regulated Pannexin-1 Channel Drives Luminal ATP Accumulation in Kidney Cysts. The FASEB Journal, 40(10). https://doi.org/10.1096/fj.202502847RR

MLA:

Skoczynski, Kathrin, et al. "HIF-Regulated Pannexin-1 Channel Drives Luminal ATP Accumulation in Kidney Cysts." The FASEB Journal 40.10 (2026).

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