| | Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathwayEdited by Beat Imhof Received 9 November 2006; received in revised form 20 December 2006; accepted 22 December 2006. published online 12 January 2007. Abstract Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1β and TNF-α markedly suppressed activity of the nephrin gene promoter in podocytes. The cytokine-initiated repression was reversible, observed on both basal and inducible expression, independent of Wilms’ tumor suppressor WT1, and caused in part via activation of the phosphatidylinositol-3-kinase/Akt pathway. These results indicated a novel mechanism by which activated macrophages participate in the induction of proteinuria in glomerular diseases. Abbreviations: PKC, protein kinase C, SEAP, secreted alkaline phosphatase, FBS, fetal bovine serum, ATRA, all-trans retinoic acid, PI3K, phosphophatidylinositol-3-kinase, TPA, 12-o-tetradecanoylphorbol-13-acetate, MϕCM, macrophage-conditioned medium, LPS, lipopolysaccharide, RT-PCR, reverse transcriptase-polymerase chain reaction, GAPDH, glyceraldehydes-3-phosphate dehydrogenase, REPON, reporter podocytes for nephrin, HGF, hepatocyte growth factor, RAR, retinoic acid receptor, RARE, retinoic acid response element Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan  Corresponding author. Fax: +81 55 273 8054.
PII: S0014-5793(07)00020-8 doi:10.1016/j.febslet.2006.12.051 © 2007 Federation of European Biochemical Societies | |
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ABSTRACT
