{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T03:07:47Z","timestamp":1762052867695,"version":"build-2065373602"},"reference-count":66,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swiss National Science Foundation","award":["310030_175561\/1","310030_184813","NCCR \u201cKidney.ch\u201d, 183774","20\/2020","SFB 1039"],"award-info":[{"award-number":["310030_175561\/1","310030_184813","NCCR \u201cKidney.ch\u201d, 183774","20\/2020","SFB 1039"]}]},{"name":"Hochschulstiftung der Universit\u00e4t Bern","award":["310030_175561\/1","310030_184813","NCCR \u201cKidney.ch\u201d, 183774","20\/2020","SFB 1039"],"award-info":[{"award-number":["310030_175561\/1","310030_184813","NCCR \u201cKidney.ch\u201d, 183774","20\/2020","SFB 1039"]}]},{"name":"German Research Foundation","award":["310030_175561\/1","310030_184813","NCCR \u201cKidney.ch\u201d, 183774","20\/2020","SFB 1039"],"award-info":[{"award-number":["310030_175561\/1","310030_184813","NCCR \u201cKidney.ch\u201d, 183774","20\/2020","SFB 1039"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Erythropoietin (Epo) is a crucial hormone regulating red blood cell number and consequently the hematocrit. Epo is mainly produced in the kidney by interstitial fibroblast-like cells. Previously, we have shown that in cultures of the immortalized mouse renal fibroblast-like cell line FAIK F3-5, sphingosine 1-phosphate (S1P), by activating S1P1 and S1P3 receptors, can stabilize hypoxia-inducible factor (HIF)-2\u03b1 and upregulate Epo mRNA and protein synthesis. In this study, we have addressed the role of intracellular iS1P derived from sphingosine kinases (Sphk) 1 and 2 on Epo synthesis in F3-5 cells and in mouse primary cultures of renal fibroblasts. We show that stable knockdown of Sphk2 in F3-5 cells increases HIF-2\u03b1 protein and Epo mRNA and protein levels, while Sphk1 knockdown leads to a reduction of hypoxia-stimulated HIF-2\u03b1 and Epo protein. A similar effect was obtained using primary cultures of renal fibroblasts isolated from wildtype mice, Sphk1\u2212\/\u2212, or Sphk2\u2212\/\u2212 mice. Furthermore, selective Sphk2 inhibitors mimicked the effect of genetic Sphk2 depletion and also upregulated HIF-2\u03b1 and Epo protein levels. The combined blockade of Sphk1 and Sphk2, using Sphk2\u2212\/\u2212 renal fibroblasts treated with the Sphk1 inhibitor PF543, resulted in reduced HIF-2\u03b1 and Epo compared to the untreated Sphk2\u2212\/\u2212 cells. Exogenous sphingosine (Sph) enhanced HIF-2\u03b1 and Epo, and this was abolished by the combined treatment with the selective S1P1 and S1P3 antagonists NIBR-0213 and TY52156, suggesting that Sph was taken up by cells and converted to iS1P and exported to then act in an autocrine manner through S1P1 and S1P3. The upregulation of HIF-2\u03b1 and Epo synthesis by Sphk2 knockdown was confirmed in the human hepatoma cell line Hep3B, which is well-established to upregulate Epo production under hypoxia. In summary, these data show that sphingolipids have diverse effects on Epo synthesis. While accumulation of intracellular Sph reduces Epo synthesis, iS1P will be exported to act through S1P1+3 to enhance Epo synthesis. Furthermore, these data suggest that selective inhibition of Sphk2 is an attractive new option to enhance Epo synthesis and thereby to reduce anemia development in chronic kidney disease.<\/jats:p>","DOI":"10.3390\/ijms23115882","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T22:04:06Z","timestamp":1653429846000},"page":"5882","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Redona","family":"Hafizi","sequence":"first","affiliation":[{"name":"Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faik","family":"Imeri","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bisera","family":"Stepanovska Tanturovska","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roxana","family":"Manaila","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Schwalm","sequence":"additional","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, University Hospital Frankfurt am Main, Goethe-University, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Trautmann","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, University Hospital Frankfurt am Main, Goethe-University, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7592-4839","authenticated-orcid":false,"given":"Roland H.","family":"Wenger","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Z\u00fcrich, CH-8057 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef","family":"Pfeilschifter","sequence":"additional","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, University Hospital Frankfurt am Main, Goethe-University, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1615-5691","authenticated-orcid":false,"given":"Andrea","family":"Huwiler","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1172\/JCI76369","article-title":"Emerging biology of sphingosine-1-phosphate: Its role in pathogenesis and therapy","volume":"125","author":"Proia","year":"2015","journal-title":"J. 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