{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T15:03:22Z","timestamp":1780067002605,"version":"3.54.0"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T00:00:00Z","timestamp":1594339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/01366, PI15\/00298, PI16\/02057, PI19\/00588, PI19\/00815, DTS18\/00032"],"award-info":[{"award-number":["PI18\/01366, PI15\/00298, PI16\/02057, PI19\/00588, PI19\/00815, DTS18\/00032"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RETIC REDinREN RD016\/0009 Fondos FEDER"],"award-info":[{"award-number":["RETIC REDinREN RD016\/0009 Fondos FEDER"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Grant Fondecyt (Conicyt Chile)","award":["1160465"],"award-info":[{"award-number":["1160465"]}]},{"name":"ERA-PerMed-JTC2018","award":["AC18\/00064"],"award-info":[{"award-number":["AC18\/00064"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a\/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NF\u03baB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.<\/jats:p>","DOI":"10.3390\/jcm9072178","type":"journal-article","created":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T09:45:31Z","timestamp":1594374331000},"page":"2178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes"],"prefix":"10.3390","volume":"9","author":[{"given":"Leticia","family":"Cuarental","sequence":"first","affiliation":[{"name":"IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Fundacion Renal I\u00f1igo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain"},{"name":"Red de Investigaci\u00f3n Renal (REDINREN), Fundacion Jimenez Diaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3340-0716","authenticated-orcid":false,"given":"Lara","family":"Vali\u00f1o-Rivas","sequence":"additional","affiliation":[{"name":"IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Fundacion Renal I\u00f1igo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain"},{"name":"Red de Investigaci\u00f3n Renal (REDINREN), Fundacion Jimenez Diaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"Nephrology Department, Centro Hospitalar Universit\u00e1rio S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moin","family":"Saleem","sequence":"additional","affiliation":[{"name":"Bristol Renal, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Mezzano","sequence":"additional","affiliation":[{"name":"Laboratorio de Nefrologia, Facultad de Medicina, Universidad Austral de Chile, 5090000 Valdivia, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-5689","authenticated-orcid":false,"given":"Ana Belen","family":"Sanz","sequence":"additional","affiliation":[{"name":"IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Fundacion Renal I\u00f1igo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain"},{"name":"Red de Investigaci\u00f3n Renal (REDINREN), Fundacion Jimenez Diaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-9523","authenticated-orcid":false,"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[{"name":"IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Fundacion Renal I\u00f1igo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain"},{"name":"Red de Investigaci\u00f3n Renal (REDINREN), Fundacion Jimenez Diaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Dolores","family":"Sanchez-Ni\u00f1o","sequence":"additional","affiliation":[{"name":"IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Fundacion Renal I\u00f1igo Alvarez de Toledo-IRSIN, 28040 Madrid, Spain"},{"name":"Red de Investigaci\u00f3n Renal (REDINREN), Fundacion Jimenez Diaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"983","DOI":"10.2215\/CJN.11761116","article-title":"Primary membranous nephropathy","volume":"12","author":"Couser","year":"2017","journal-title":"Clin. 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