title: Non-canonical NFκB activation promotes chemokine expression in podocytes.
abstract: TNF-like weak inducer of apoptosis (TWEAK) receptor Fn14 is expressed by podocytes and Fn14 deficiency protects from experimental proteinuric kidney disease. However, the downstream effectors of TWEAK/Fn14 in podocytes are poorly characterized. We have explored TWEAK activation of non-canonical NFκB signaling in cultured podocytes. In cultured podocytes, TWEAK increased the expression of the chemokines CCL21, CCL19 and RANTES in a time-dependent manner. The inhibitor of canonical NFκB activation parthenolide inhibited the CCL19 and the early RANTES responses, but not the CCL21 or late RANTES responses. In this regard, TWEAK induced non-canonical NFκB activation in podocytes, characterized by NFκB2/p100 processing to NFκB2/p52 and nuclear migration of RelB/p52. Silencing by a specific siRNA of NIK, the upstream kinase of the non-canonical NFκB pathway, prevented CCL21 upregulation but did not modulate CCL19 or RANTES expression in response to TWEAK, thus establishing CCL21 as a non-canonical NFκB target in podocytes. Increased kidney Fn14 and CCL21 expression was also observed in rat proteinuric kidney disease induced by puromycin, and was localized to podocytes. In conclusion, TWEAK activates the non-canonical NFκB pathway in podocytes, leading to upregulation of CCL21 expression. The non-canonical NFκB pathway should be explored as a potential therapeutic target in proteinuric kidney disease.
authors.affiliation: IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Valiño-Rivas
authors.affiliation: IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Gonzalez-Lafuente
authors.affiliation: IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid and Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.|REDINREN, Madrid, Spain.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Sanchez-Niño
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000235:genetics / Q000378:metabolism; D054421:Chemokine CCL21 / Q000096:biosynthesis* / Q000235:genetics; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D000074049:Cytokine TWEAK / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011507:Proteinuria / Q000188:drug therapy; D011921:Rats, Inbred WKY; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy; D015398:Signal Transduction
chemical_list: C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D018946:Chemokine CCL5; D000074049:Cytokine TWEAK; D016328:NF-kappa B; C109743:TNFSF12 protein, human