title: Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy.
abstract: BACKGROUND
  The molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely elucidated but the renin-angiotensin system (RAS) is involved. Idiopathic membranous nephropathy (MN), a proteinuric disease, may progress to renal failure. Our aim was to investigate the localization of RAS components in MN and their correlation with profibrotic parameters and renal injury.
  
  
  METHODS
  Renal biopsies from 20 patients with MN (11 with progressive disease) were studied for the expression of RAS components [angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)] by immunohistochemistry. Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by alpha-smooth muscle actin (alpha-SMA) staining.
  
  
  RESULTS
  ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in alpha-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-beta and PDGF mRNAs were up-regulated mainly in cortical tubular epithelial cells in progressive disease (P < 0.01) and correlated with the myofibroblast transdifferentiation (r = 0.8, P < 0.01 for TGF-beta; r = 0.6, P < 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expression was associated with the tubular expression of these pro-fibrogenic factors, and with the interstitial infiltration and myofibroblast activation.
  
  
  CONCLUSIONS
  Intrarenal RAS is selectively activated in progressive MN. De novo expression of ACE at sites of tubulointerstitial injury suggests that the in situ Ang II generation could participate in tubular TGF-beta up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.
authors.affiliation: Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile. smezzano@uach.cl
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Mezzano
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Aros
authors.forename: Alejandra
authors.initials: A
authors.lastname: Droguett
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Burgos
authors.forename: Leopoldo G
authors.initials: LG
authors.lastname: Ardiles
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Flores
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Vío
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000077214:Becaplermin; D005347:Fibroblasts / Q000473:pathology; D015433:Glomerulonephritis, Membranous / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012084:Renin-Angiotensin System; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D000077214:Becaplermin