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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1399248
This article is part of the Research Topic Insights in Cardiovascular and Smooth Muscle Pharmacology: 2023 View all 9 articles

Activation of PERK/eIF2α/ATF4/CHOP branch of endoplasmic reticulum stress response and cooperation between HIF-1α and ATF4 promotes Daprodustat-induced vascular calcification

Provisionally accepted
Andrea Tóth Andrea Tóth 1Gréta Lente Gréta Lente 1Dávid M. Csiki Dávid M. Csiki 1Enikő Balogh Enikő Balogh 1Arpad Szoor Arpad Szoor 2Béla J. Nagy Béla J. Nagy 3Viktória Jeney Viktória Jeney 1*
  • 1 University of Debrecen, MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, Debrecen, Hungary
  • 2 Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
  • 3 Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

The final, formatted version of the article will be published soon.

    Introduction: Vascular calcification is accelerated in patients with chronic kidney disease (CKD) and increases the risk of cardiovascular events. CKD is frequently associated with anemia. Daprodustat (DPD) is a prolyl hydroxylase inhibitor for the treatment of CKD-associated anemia that enhances erythropoiesis through the activation of the hypoxia-inducible factor 1 (HIF-1) pathway. Studies showed that DPD promotes osteogenic differentiation of human aortic smooth muscle cells (HAoSMCs) and increases aorta calcification in mice with CKD. HIF-1 activation has been linked with endoplasmic reticulum (ER) stress; therefore, here we investigated the potential contribution of ER stress, particularly activating transcription factor 4 (ATF4), to the pro-calcification effect of DPD. Methods: Here, we used an adenine-induced CKD mouse model and HAoSMCs as an in vitro vascular calcification model to study the effect of DPD. Results: DPD treatment (15 mg/kg/day) corrects anemia but increases the expression of hypoxia (Glut1, VEGFA), ER stress (ATF4, CHOP, GRP78), and osteo-/chondrogenic (Runx2, Sox9, BMP2, Msx2) markers and accelerates aorta and kidney calcification in CKD mice. DPD activates the PERK/eIF2α/ATF4/CHOP pathway and promotes high phosphate-induced osteo-/chondrogenic differentiation of HAoSMCs. Inhibition of ER stress with 4-PBA or silencing of ATF4 attenuates HAoSMC calcification. DPD-induced ATF4 expression is abolished in the absence of HIF-1α; however, knockdown of ATF4 does not affect HIF-1α expression. Conclusion: We concluded that DPD induces ER stress in vitro and in vivo, in which ATF4 serves as a downstream effector of HIF-1 activation. Targeting ATF4 could be a potential therapeutic approach to attenuate the pro-calcific effect of DPD.

    Keywords: Chronic kidney disease (CKD), Vascular Calcification, Prolyl hydroxylase inhibitor, Hypoxia-Inducible Factor 1, Endoplasmic Reticulum Stress, ATF4, Daprodustat

    Received: 11 Mar 2024; Accepted: 17 Jul 2024.

    Copyright: © 2024 Tóth, Lente, Csiki, Balogh, Szoor, Nagy and Jeney. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Viktória Jeney, University of Debrecen, MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, Debrecen, Hungary

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