Lethal activity of FADD death domain in renal tubular epithelial cells

Kidney Int. 2006 Jun;69(12):2205-11. doi: 10.1038/sj.ki.5000444. Epub 2006 May 3.


Fas-associated death domain (FADD) is an adaptor protein that is required for the transmission of the death signal from lethal receptors of the tumor necrosis factor superfamily. FADD contains a death domain (DD) and a death effector domain (DED). As death receptors contribute to renal tubular injury and tubular cell FADD increases in acute renal failure, we have studied the function of FADD in tubular epithelium. FADD expression was studied in kidney samples from mice. In order to study the contribution of FADD to renal tubular cell survival, FADD or FADD-DD were overexpressed in murine tubular epithelium. FADD is expressed in renal tubules of the healthy kidney. Both FADD and FADD-DD induce apoptosis in primary cultures of murine tubular epithelium and in the murine cortical tubular cell line. Death induced by FADD-DD has apoptotic morphology, but differs from death receptor-induced apoptosis in that it is not blocked by inhibitors of caspases. Neither an inhibitor of serine proteases nor overexpression of antiapoptotic BclxL prevented cell death. However, the combination of caspase and serine protease inhibition was protective. FADD and FADD-DD overexpression decreased nuclear factor kappa B activity. These data suggest that FADD has a death regulatory function in renal tubular cells that is independent of death receptors. FADD-DD is sufficient to induce apoptosis in these cells. This information is relevant to understanding the role of FADD in tubular injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / physiopathology
  • Adaptor Proteins, Signal Transducing / analysis
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Cells, Cultured
  • Epithelial Cells / chemistry*
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Epithelial Cells / physiology
  • Fas-Associated Death Domain Protein
  • Gene Expression Regulation
  • Kidney Tubules / chemistry*
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Kidney Tubules / physiopathology
  • Mice
  • Mice, Inbred Strains
  • NF-kappa B / physiology
  • Protein Structure, Tertiary / genetics
  • Protein Structure, Tertiary / physiology
  • Receptors, Tumor Necrosis Factor / physiology
  • Serine Proteinase Inhibitors


  • Adaptor Proteins, Signal Transducing
  • Caspase Inhibitors
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • Serine Proteinase Inhibitors
  • Caspases