Abstract
Inhibition of the prolyl-4-hydroxylase domain (PHD) enzymes, leading to the stabilization of hypoxia-inducible factor (HIF) α as well as to the stimulation of erythropoietin (Epo) synthesis, is the functional mechanism of the new anti-anemia drug roxadustat. Little is known about the effects of roxadustat on the Epo-producing cell pool. To gain further insights into the function of PHD inhibitors, we characterized the abundance of mesenchymal stem cell (MSC)-like cells after roxadustat treatment of mice. The number of Sca-1+ mesenchymal cells following roxadustat treatment increased exclusively in the kidneys. Isolated Sca-1+ cells demonstrated typical features of MSC-like cells, including adherence to tissue culture plates, trilineage differentiation potential, and expression of MSC markers. Kidney-derived Sca-1+ MSC-like cells were cultured for up to 21 days. Within the first few days in culture, cells stabilized HIF-1α and HIF-2α and temporarily increased Epo production upon incubation in hypoxia. In summary, we have identified a Sca-1+ MSC-like cell population that is involved in renal Epo production and might contribute to the strong anti-anemic effect of the PHD inhibitor roxadustat.
Highlights
The oxygen-sensitive hypoxia-inducible factor (HIF) pathway plays a central role in cellular adaptation to limited oxygen supply [1]
Roxadustat Treatment Increases the Number of stem cell antigen-1 (Sca-1)-Positive Cells in the Kidneys
Aside from the increase in Epo in the kidneys, we found increased mRNA levels of the carbonic anhydrase IX (CAIX) and plasminogen activator inhibitor 1 (PAI1) in the liver and lungs, respectively, but not in the kidneys
Summary
The oxygen-sensitive hypoxia-inducible factor (HIF) pathway plays a central role in cellular adaptation to limited oxygen supply [1]. The protein stability of the HIFα subunit is regulated by oxygen- and iron-dependent prolyl-4-hydroxylase domain (PHD) enzymes [2]. Local tissue hypoxia is a major factor triggering erythropoietin (Epo) production [3]. The hypoxic induction of Epo is tightly connected to the HIF pathway, since Epo is almost exclusively regulated on the transcriptional level via the binding of HIF to various regulatory elements of the Epo gene [4]. The kidney is the main site of Epo synthesis in adults. Pathological conditions such as chronic kidney disease (CKD) impair the renal ability to synthesize Epo, resulting in hypoproliferative renal anemia. The administration of recombinant Epo represents the current standard of care for patients with renal anemia [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
