TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury

FASEB J. 2005 Oct;19(12):1637-45. doi: 10.1096/fj.05-3841com.


In normal kidney, TNFR1 is expressed in glomerular and peritubular capillary EC, and some tubular cells, and colocalizes with inactive apoptosis signal-regulating kinase-1 (ASK1) phosphorylated at serine 967. Biopsies of rejecting or ischemic renal allografts, which show both tubular cell injury and proliferation, display down-regulation of TNFR1 and activation of ASK1 as well as up-regulation of TNFR2 on tubular cells, where it colocalizes with phosphorylated endothelial/epithelial tyrosine kinase (Etk). We have exploited receptor-selective muteins and evaluated phosphorylation of receptor-specific kinases to study TNF responses in situ. In organ culture, a TNFR1-specific mutein changes phosphorylation of ASK1 to threonine 845, indicative of kinase activation. A TNFR2-specific mutein down-regulates TNFR1 in glomerular EC, up-regulates TNFR2 and Etk in tubular cells, and induces phosphorylation of Etk. Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1. Wild-type TNF and TNFR1-specific mutein trigger tubular cell apoptosis whereas wild-type TNF and TNFR2-specific mutein induce tubular cells to express proliferating cell nuclear antigen. Differential activation of ASK1 and Etk by regulated TNFRs in patient-derived materials provides an explanation for diverse and opposing responses to TNF at distinct sites, and an in situ bioassay of TNFR signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis
  • Biological Assay
  • Biopsy
  • Cell Proliferation
  • Down-Regulation
  • Enzyme Activation
  • Humans
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Kidney / injuries*
  • Kidney / metabolism*
  • Kidney Diseases / pathology*
  • Kidney Neoplasms / pathology
  • Kidney Transplantation
  • Kidney Tubules / cytology
  • Kidney Tubules / metabolism
  • MAP Kinase Kinase Kinase 5 / biosynthesis
  • Microscopy, Confocal
  • Models, Biological
  • Organ Culture Techniques
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / physiology*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / physiology*
  • Signal Transduction*
  • Threonine / chemistry
  • Up-Regulation


  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Threonine
  • BMX protein, human
  • Protein-Tyrosine Kinases
  • MAP Kinase Kinase Kinase 5