{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:31:17Z","timestamp":1787639477984,"version":"build-2736575974"},"reference-count":34,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T00:00:00Z","timestamp":1703808000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). VC is a gene\u2010regulated process similar to osteogenic differentiation. There are still no convincing schemes to prevent and reduce the development of VC. It has been reported that hypoxia\u2010inducing factor 1\u03b1 (HIF\u20101\u03b1) and endothelin\u20101(ET\u20101) are related to VC. In this study, we found that the expression of ET\u20101 and HIF\u20101\u03b1 was enhanced after VC, the interaction between HIF\u20101\u03b1 and ET\u20101 was confirmed by CO\u2010IP and luciferase experiments. We found that ET\u20101 was an upregulated differential gene of calcified vascular smooth muscle cells (VSMCs) through gene sequencing. However, hypoxia\u2010inducing factor 2\u03b1 (HIF\u20102\u03b1) and HIF\u20101\u03b1 have antagonistic effects on each other. HIF\u20101\u03b1 is a pro\u2010inflammatory cytokine, and HIF\u20102\u03b1 can improve inflammation and fibrosis. Roxadustat, as a selective PHD3 inhibitor, preferentially activates HIF\u20102\u03b1. It is still unclear whether roxadustat improves VC in CKD by regulating the expression of HIF\u20102\u03b1\/HIF\u20101\u03b1. Alizarin red staining and western blot as well as immunohistochemical results showed that roxadustat could significantly reduce the degree of vascular and VSMCs calcification in CKD rats. Serum HIF\u20101\u03b1 and ET\u20101 were significantly decreased after roxadustat treatment. In addition, western blot results showed that roxadustat could decrease the expression of HIF\u20101\u03b1 and ET\u20101 in vascular tissues and calcified VSMC, but HIF\u20102\u03b1 expression significantly increased. Interestingly, our study confirmed that activation of HIF\u20101\u03b1 or inhibition of HIF\u20102\u03b1 reversed the ameliorating effect of roxadustat on VC, proving that the effect mediated by roxadustat is HIF\u20102\u03b1\/HIF\u20101\u03b1 dependent. We have demonstrated for the first time that roxadustat improves VC in CKD rats by regulating HIF\u20102\u03b1\/HIF\u20101\u03b1, thus providing a new idea for the application of roxadustat in VC of CKD.<\/jats:p>","DOI":"10.1002\/tox.24116","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T09:25:59Z","timestamp":1703841959000},"page":"2363-2373","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Roxadustat ameliorates vascular calcification in <scp>CKD<\/scp> rats by regulating <scp>HIF<\/scp>\u20102\u03b1\/<scp>HIF<\/scp>\u20101\u03b1"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4443-0577","authenticated-orcid":false,"given":"Yujing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hemodialysis Haikou Affiliated Hospital of Central South University Xiangya School of Medicine  Haikou 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