title: The proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulointerstitial architecture.
abstract: OBJECTIVE
  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.
authors.affiliation: Nephropathology, Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hainz
authors.forename: Susanne
authors.initials: S
authors.lastname: Thomas
authors.forename: Kirsten
authors.initials: K
authors.lastname: Neubert
authors.forename: Silke
authors.initials: S
authors.lastname: Meister
authors.forename: Kerstin
authors.initials: K
authors.lastname: Benz
authors.forename: Manfred
authors.initials: M
authors.lastname: Rauh
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.forename: Michael
authors.initials: M
authors.lastname: Wiesener
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008181:Lupus Nephritis / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D024141:Collagen Type IV; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex