Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy.
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.
Mezzano
Sergio A
SA
Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile. smezzano@uach.cl
Aros
Claudio A
CA
Droguett
Alejandra
A
Burgos
M Eugenia
ME
Ardiles
Leopoldo G
LG
Flores
Claudio A
CA
Carpio
Daniel
D
Vío
Carlos P
CP
Ruiz-Ortega
Marta
M
Egido
Jesús
J
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
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D000077214:Becaplermin