The proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulointerstitial architecture

Nephron Exp Nephrol. 2012;120(2):e47-58. doi: 10.1159/000334955. Epub 2012 Jan 26.


Background/aims: Crucial steps in the initiation of lupus nephritis are the deposition of (auto-)antibodies and consequent complement activation. In spite of aggressive treatment patients may develop terminal renal failure. Therefore, new treatment strategies are needed. In extension to our previously published data we here analyzed the potential renoprotective mechanisms of bortezomib (BZ) in experimental lupus nephritis by focusing on morphological changes.

Methods: Female NZB×NZW F1 mice develop lupus-like disease with extensive nephritis that finally leads to lethal renal failure. Treatment with 0.75 mg/kg BZ i.v. or placebo (PBS) twice per week started at 18 or 24 weeks of age. Antibody production was measured with ELISA and kidney damage was determined by quantitative morphological and immunohistochemical methods.

Results: BZ treatment completely inhibited antibody production in both BZ-treated groups and prevented the development of nephritis in comparison to PBS-treated animals. Glomerular and tubulointerstitial damage scores, collagen IV expression, mean glomerular volume as well as tubulointerstitial proliferation and apoptosis were significantly lower after BZ treatment. Glomerular ultrastructure and in particular podocyte damage and loss were prevented by BZ treatment.

Conclusions: BZ effectively prevents the development of nephritis in the NZB/W F1 mouse model. Specific protection of podocyte ultrastructure may critically contribute to renoprotection by BZ, which may also represent a potential new treatment option in human lupus nephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Boronic Acids / administration & dosage
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Collagen Type IV / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Immunohistochemistry
  • Injections, Intravenous
  • Kidney Glomerulus / drug effects*
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / ultrastructure
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism
  • Kidney Tubules / ultrastructure
  • Lupus Nephritis / mortality
  • Lupus Nephritis / physiopathology
  • Lupus Nephritis / prevention & control*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred Strains
  • Microscopy, Electron
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Pyrazines / administration & dosage
  • Pyrazines / pharmacology*
  • Survival Rate
  • Time Factors
  • Treatment Outcome


  • Boronic Acids
  • Collagen Type IV
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib
  • Proteasome Endopeptidase Complex