Transcriptional Suppression of Nephrin in Podocytes by Macrophages: Roles of Inflammatory Cytokines and Involvement of the PI3K/Akt Pathway

FEBS Lett. 2007 Feb 6;581(3):421-6. doi: 10.1016/j.febslet.2006.12.051. Epub 2007 Jan 12.

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-1beta and TNF-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication
  • Cells, Cultured
  • Cytokines / metabolism
  • Cytokines / pharmacology
  • Down-Regulation / drug effects
  • Humans
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / pharmacology
  • Interleukin-1beta / metabolism
  • Interleukin-1beta / pharmacology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Membrane Proteins / genetics*
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Podocytes / drug effects
  • Podocytes / metabolism*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Cytokines
  • Inflammation Mediators
  • Interleukin-1beta
  • Membrane Proteins
  • Tumor Necrosis Factor-alpha
  • nephrin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt