title: C5b-9 does not mediate chronic tubulointerstitial disease in the absence of proteinuria.
abstract: BACKGROUND
  In nephrotic glomerular diseases, the intratubular assembly of the membrane attack complex (C5b-9) is one of the principal mediators of chronic tubulointerstitial damage. Here, we examined whether C5b-9 has a pathogenic role in tubulointerstitial disease in the absence of proteinuria.
  
  
  METHODS
  Three pathophysiologically distinct models of nonproteinuric chronic tubulointerstitial disease were induced in Piebald-Viral-Glaxo (PVG) rats, with or without C6 deficiency (C6+ and C6): (1) unilateral ureteric obstruction (UUO, days 1, 3, 6, 14, and 21; N= 5-6/group); (2) cyclosporine (CsA) nephropathy (15 mg/kg SC daily with 0.05% sodium diet; day 14, 35 N= 9/group); and (3) streptozotocin (STZ)-induced diabetes (day 90, N= 8/group).
  
  
  RESULTS
  The peritubular deposition of C5b-9 increased in all three models. In UUO, the number of vimentin-positive tubules, interstitial volume expansion, and monocyte accumulation were similar in both the C6+ and C6- groups at all time points. There was a trend toward an earlier peak in myofibroblast accumulation in C6- rats with UUO (d3 vs. d6; P= 0.05), but this did not prevent fibrosis at later time points. In CsA nephropathy, cortical tubulointerstitial damage was also similar in both C6+ and C6- groups on day 14, despite equivalent CsA trough levels. Finally, in STZ-induced diabetes, rats did not develop proteinuria, and tubulointerstitial disease (distal tubule glycogen nephrosis, interstitial volume expansion, and tubular dilatation) was not altered by C6 deficiency.
  
  
  CONCLUSIONS
  These data suggest that, in contrast to proteinuric states, C5b-9 does not have a significant impact on the progression of tubulointerstitial damage in nonproteinuric chronic renal disease.
authors.affiliation: Division of Nephrology, University of Washington Medical Center, Seattle, Washington, USA. g.rangan@wmi.usyd.edu.au
authors.forename: Gopala K
authors.initials: GK
authors.lastname: Rangan
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pippin
authors.forename: Jason D
authors.initials: JD
authors.lastname: Coombes
authors.forename: William G
authors.initials: WG
authors.lastname: Couser
mesh_terms: D000818:Animals; D002908:Chronic Disease; D015938:Complement Membrane Attack Complex / Q000502:physiology*; D016572:Cyclosporine / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000473:pathology*; D009395:Nephritis, Interstitial / Q000473:pathology*; D011507:Proteinuria / Q000473:pathology*; D051381:Rats; D013311:Streptozocin; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: D015938:Complement Membrane Attack Complex; D016326:Extracellular Matrix Proteins; D013311:Streptozocin; D016572:Cyclosporine