Non-canonical NF?B 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 NF?B 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 NF?B 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 NF?B activation in podocytes, characterized by NF?B2/p100 processing to NF?B2/p52 and nuclear migration of RelB/p52. Silencing by a specific siRNA of NIK, the upstream kinase of the non-canonical NF?B pathway, prevented CCL21 upregulation but did not modulate CCL19 or RANTES expression in response to TWEAK, thus establishing CCL21 as a non-canonical NF?B 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 NF?B pathway in podocytes, leading to upregulation of CCL21 expression. The non-canonical NF?B pathway should be explored as a potential therapeutic target in proteinuric kidney disease.

SUBMITTER: Valino-Rivas L 

PROVIDER: S-EPMC4926283 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature