title: Proximal tubular cells promote fibrogenesis by TGF-beta1-mediated induction of peritubular myofibroblasts.
abstract: BACKGROUND
  In proteinuric nephropathies with increasingly severe defects of the glomerular filtering barrier, interstitial fibrogenesis is a major effector of scarring. An early event in this process is the peritubular accumulation of myofibroblasts that express alpha-smooth muscle actin (alpha-SMA) and contribute to abnormal matrix production. Common trigger factors are poorly understood. Enhanced protein trafficking may play a role by up-regulating inflammatory and fibrogenic genes in proximal tubular cells.
  
  
  METHODS
  The remnant kidney model in rats was used to (1) analyze interactions between activated proximal tubular cells, peritubular cells expressing the myofibroblast marker, and inflammatory cells at time intervals (days 7, 14, and 30) after surgery, and (2) evaluate the effects of angiotensin-converting enzyme inhibitor (ACEi) on protein trafficking, fibrogenic signaling, and alpha-SMA expression.
  
  
  RESULTS
  Abnormal uptake of ultrafiltered proteins by proximal tubular cells (IgG staining) occurred at an early stage (day 7) and was subsequently associated with macrophage and alpha-SMA+ cell accumulation into the peritubular interstitium. alpha-SMA+ cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-beta1 (TGF-beta1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal alpha-SMA staining also was found in the tubular cells and in peritubular endothelial cells on semithin ultracryosections. ACEi prevented both proteinuria and abnormal protein accumulation in tubular cells, as well as the inflammatory and fibrogenic reaction with peritubular alpha-SMA expression.
  
  
  CONCLUSIONS
  Profibrogenic signaling from both proximal tubular cells on challenge with filtered protein and inflammatory cells is implicated as a key candidate trigger of progressive tubulointerstitial injury.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Bergamo, Italy. abbate@marionegri.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Abbate
authors.forename: Carla
authors.initials: C
authors.lastname: Zoja
authors.forename: Daniela
authors.initials: D
authors.lastname: Rottoli
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Susanna
authors.initials: S
authors.lastname: Tomasoni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000199:Actins / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology*; D005355:Fibrosis; D007074:Immunoglobulin G / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000473:pathology* / Q000503:physiopathology* / Q000648:ultrastructure; D017706:Lisinopril / Q000494:pharmacology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D011507:Proteinuria / Q000652:urine; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
chemical_list: D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D007074:Immunoglobulin G; D011506:Proteins; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017706:Lisinopril