Next Article in Journal
A Small Compound KJ-28d Enhances the Sensitivity of Non-Small Cell Lung Cancer to Radio- and Chemotherapy
Previous Article in Journal
The Regional Specific Alterations in BBB Permeability are Relevant to the Differential Responses of 67-kDa LR Expression in Endothelial Cells and Astrocytes Following Status Epilepticus
Open AccessArticle

Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

by Wei-Ting Chang 1,2,3, Yi-Ching Lo 4, Zi-Han Gao 5 and Sheng-Nan Wu 5,6,7,*
1
Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 71004 Taiwan
2
Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 71004, Taiwan
3
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
4
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
5
Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan
6
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan
7
Department of Basic Medical Sciences, China Medical University Hospital, Taichung 40402, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 6027; https://doi.org/10.3390/ijms20236027
Received: 31 October 2019 / Revised: 18 November 2019 / Accepted: 25 November 2019 / Published: 29 November 2019
(This article belongs to the Section Biochemistry)
Roxadustat (FG-4592), an analog of 2-oxoglutarate, is an orally-administered, heterocyclic small molecule known to be an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase. However, none of the studies have thus far thoroughly investigated its possible perturbations on membrane ion currents in endocrine or heart cells. In our studies, the whole-cell current recordings of the patch-clamp technique showed that the presence of roxadustat effectively and differentially suppressed the peak and late components of IK(DR) amplitude in response to membrane depolarization in pituitary tumor (GH3) cells with an IC50 value of 5.71 and 1.32 μM, respectively. The current inactivation of IK(DR) elicited by 10-sec membrane depolarization became raised in the presence of roxadustatt. When cells were exposed to either CoCl2 or deferoxamine (DFO), the IK(DR) elicited by membrane depolarization was not modified; however, nonactin, a K+-selective ionophore, in continued presence of roxadustat, attenuated roxadustat-mediated inhibition of the amplitude. The steady-state inactivation of IK(DR) could be constructed in the presence of roxadustat. Recovery of IK(DR) block by roxadustat (3 and 10 μM) could be fitted by a single exponential with 382 and 523 msec, respectively. The roxadustat addition slightly suppressed erg-mediated K+ or hyperpolarization-activated cation currents. This drug also decreased the peak amplitude of voltage-gated Na+ current with a slowing in inactivation rate of the current. Likewise, in H9c2 heart-derived cells, the addition of roxadustat suppressed IK(DR) amplitude in combination with the shortening in inactivation time course of the current. In high glucose-treated H9c2 cells, roxadustat-mediated inhibition of IK(DR) remained unchanged. Collectively, despite its suppression of HIF prolyl hydroxylase, inhibitory actions of roxadustat on different types of ionic currents possibly in a non-genomic fashion might provide another yet unidentified mechanism through which cellular functions are seriously perturbed, if similar findings occur in vivo. View Full-Text
Keywords: roxadustat; delayed-rectifier K+ current; voltage-gated Na+ current; current kinetics; pituitary cell and heart cell roxadustat; delayed-rectifier K+ current; voltage-gated Na+ current; current kinetics; pituitary cell and heart cell
Show Figures

Figure 1

MDPI and ACS Style

Chang, W.-T.; Lo, Y.-C.; Gao, Z.-H.; Wu, S.-N. Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action. Int. J. Mol. Sci. 2019, 20, 6027.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop