{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:03:47Z","timestamp":1779145427058,"version":"3.51.4"},"reference-count":70,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_175561\/1"],"award-info":[{"award-number":["310030_175561\/1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["20\/2020"],"award-info":[{"award-number":["20\/2020"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["SFB 1039"],"award-info":[{"award-number":["SFB 1039"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hochschulstiftung der Universit\u00e4t Bern","award":["310030_175561\/1"],"award-info":[{"award-number":["310030_175561\/1"]}]},{"name":"Hochschulstiftung der Universit\u00e4t Bern","award":["20\/2020"],"award-info":[{"award-number":["20\/2020"]}]},{"name":"Hochschulstiftung der Universit\u00e4t Bern","award":["SFB 1039"],"award-info":[{"award-number":["SFB 1039"]}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["310030_175561\/1"],"award-info":[{"award-number":["310030_175561\/1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["20\/2020"],"award-info":[{"award-number":["20\/2020"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["SFB 1039"],"award-info":[{"award-number":["SFB 1039"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sphingosine 1-phosphate (S1P) lyase (SPL, Sgpl1) is an ER-associated enzyme that irreversibly degrades the bioactive lipid, S1P, and thereby regulates multiple cellular functions attributed to S1P. Biallelic mutations in the human Sglp1 gene lead to a severe form of a particular steroid-resistant nephrotic syndrome, suggesting that the SPL is critically involved in maintaining the glomerular ultrafiltration barrier, which is mainly built by glomerular podocytes. In this study, we have investigated the molecular effects of SPL knockdown (kd) in human podocytes to better understand the mechanism underlying nephrotic syndrome in patients. A stable SPL-kd cell line of human podocytes was generated by the lentiviral shRNA transduction method and was characterized for reduced SPL mRNA and protein levels and increased S1P levels. This cell line was further studied for changes in those podocyte-specific proteins that are known to regulate the ultrafiltration barrier. We show here that SPL-kd leads to the downregulation of the nephrin protein and mRNA expression, as well as the Wilms tumor suppressor gene 1 (WT1), which is a key transcription factor regulating nephrin expression. Mechanistically, SPL-kd resulted in increased total cellular protein kinase C (PKC) activity, while the stable downregulation of PKC\u03b4 revealed increased nephrin expression. Furthermore, the pro-inflammatory cytokine, interleukin 6 (IL-6), also reduced WT1 and nephrin expression. In addition, IL-6 caused increased PKC\u03b4 Thr505 phosphorylation, suggesting enzyme activation. Altogether, these data demonstrate that nephrin is a critical factor downregulated by the loss of SPL, which may directly cause podocyte foot process effacement as observed in mice and humans, leading to albuminuria, a hallmark of nephrotic syndrome. Furthermore, our in vitro data suggest that PKC\u03b4 could represent a new possible pharmacological target for the treatment of a nephrotic syndrome induced by SPL mutations.<\/jats:p>","DOI":"10.3390\/ijms24043267","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:01:45Z","timestamp":1675825305000},"page":"3267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Loss of S1P Lyase Expression in Human Podocytes Causes a Reduction in Nephrin Expression That Involves PKC\u03b4 Activation"],"prefix":"10.3390","volume":"24","author":[{"given":"Faik","family":"Imeri","sequence":"first","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":"Hermann","family":"Pavenst\u00e4dt","sequence":"additional","affiliation":[{"name":"Medizinische Klinik D, University Hospital M\u00fcnster, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef","family":"Pfeilschifter","sequence":"additional","affiliation":[{"name":"Pharmazentrum Frankfurt\/ZAFES, University Hospital, Goethe University Frankfurt am Main, 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":[[2023,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1152\/physrev.00020.2002","article-title":"Cell Biology of the Glomerular Podocyte","volume":"83","author":"Kriz","year":"2003","journal-title":"Physiol. 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