Exclusive expression of transmembrane TNF aggravates acute glomerulonephritis despite reduced leukocyte infiltration and inflammation

Kidney Int. 2019 Jan;95(1):75-93. doi: 10.1016/j.kint.2018.08.012. Epub 2018 Oct 30.


Tumor necrosis factor-α (TNF) is a cytokine mediating inflammatory kidney diseases such as immune complex glomerulonephritis. Its two receptors, TNFR1 and TNFR2, play distinct roles in this process, with TNFR2 strongly required for induction of disease. In contrast to soluble TNF (sTNF), transmembrane TNF robustly activates TNFR2. Thus, we examined the functional role of transmembrane TNF by inducing heterologous nephrotoxic serum nephritis in wild-type and transgenic TNFΔ1-9,K11E knock-in mice expressing transmembrane TNF but no sTNF (memTNF mice). Compared to wild-type, nephritis was exacerbated in memTNF mice on day 5, indicated by increased albuminuria, higher serum urea levels, and more pronounced glomerular deposits, together with higher numbers of dying and proliferating glomerular cells. This was associated with greater loss of glomerular endothelial cells, increased podocyte stress, and signs of augmented necroptosis in memTNF kidneys. Aggravation of nephritis was dependent on transmembrane TNF expression in parenchymal cells, but not leukocytes. Surprisingly, increased kidney injury was associated with reduced renal leukocyte infiltration in memTNF mice, which correlated with decreased renal mRNA expression of pro-inflammatory mediators. This effect was also present in isolated memTNF glomeruli stimulated with interleukin-1β in vitro. Thus, uncleaved transmembrane TNF is an important mediator of renal tissue damage characterized by increased renal cell death and loss of glomerular endothelial cells in murine glomerulonephritis. In contrast, sTNF predominantly mediates renal leukocyte recruitment and inflammation. These findings highlight the importance of transmembrane TNF in inflammatory kidney disease as a possible therapeutic target.

Keywords: cell death; cytokines; glomerulonephritis; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biopsy
  • Cell Line
  • Cell Membrane / metabolism*
  • Datasets as Topic
  • Disease Models, Animal
  • Endothelial Cells / cytology
  • Endothelial Cells / pathology
  • Gene Knock-In Techniques
  • Glomerulonephritis / immunology
  • Glomerulonephritis / pathology*
  • Humans
  • Interleukin-1beta / immunology
  • Kidney Glomerulus / cytology
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology*
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*


  • Interleukin-1beta
  • Receptors, Tumor Necrosis Factor, Type II
  • TNF protein, human
  • Tnf protein, mouse
  • Tumor Necrosis Factor-alpha