title: Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy.
abstract: BACKGROUND
  Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis.
  
  
  METHODS
  Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35. Infiltrating mononuclear cells were characterized by immunohistochemistry. The kidney infiltrating T lymphocytes were phenotyped by flow cytometry. Urinary levels of Th-1/ Th-2 cytokines, of monocyte chemoattractant protein-1 and of active transforming growth factor-beta (TGF-beta) were measured. Tissue expression of phosphorylated smad 2/3 protein was used to examine the TGF-beta signalling pathway.
  
  
  RESULTS
  In AA rats, monocytes/macrophages and T lymphocytes predominantly infiltrated areas of necrotic proximal tubular cells. The coexpressions of ED1 and/or Ki-67/MHCII by infiltrating cells reflected monocyte/macrophage proliferation and their activation, respectively. The accumulation of cytotoxic T lymphocytes was attested by severe signs of CD8+ cell tubulitis. The CD8/E-cadherin costaining confirmed intrarenal homing of CD8+CD103+ cells. Urinary levels of proinflammatory cytokines and of active TGF-beta significantly increased at Days 10 and 35. An early and persistent nuclear overexpression of phosphorylated smad 2/3 protein was detected in tubular and interstitial compartments.
  
  
  CONCLUSIONS
  An early and massive interstitial inflammation characterized by activated monocytes/macrophages and cytotoxic CD8+CD103+ T lymphocytes is demonstrated for the first time during the progression of experimental AAN. The involvement in an interstitial fibrosis onset of active TGF-beta is highly suggested, at least via the psmad 2/3 intracellular signalling pathway.
authors.affiliation: Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Pozdzik
authors.forename: Isabelle J
authors.initials: IJ
authors.lastname: Salmon
authors.forename: Cécile P
authors.initials: CP
authors.lastname: Husson
authors.forename: Christine
authors.initials: C
authors.lastname: Decaestecker
authors.forename: Edith
authors.initials: E
authors.lastname: Rogier
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Bourgeade
authors.forename: Monique M
authors.initials: MM
authors.lastname: Deschodt-Lanckman
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanherweghem
authors.forename: Joëlle L
authors.initials: JL
authors.lastname: Nortier
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C000228:aristolochic acid I