TY - JOUR
T1 - Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy
AU - Mezzano, Sergio A.
AU - Aros, Claudio A.
AU - Droguett, Alejandra
AU - Burgos, M. Eugenia
AU - Ardiles, Leopoldo G.
AU - Flores, Claudio A.
AU - Carpio, Daniel
AU - Vío, Carlos P.
AU - Ruiz-Ortega, Marta
AU - Egido, Jesús
PY - 2003/10
Y1 - 2003/10
N2 - 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-β (TGF-β) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by α-smooth muscle actin (α-SMA) staining. Results. ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in α-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-β 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-β; 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 profibrogenic factors, and with the interstitial infiltration and myofibroblast activation. Conclusion. 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-β up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.
AB - 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-β (TGF-β) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by α-smooth muscle actin (α-SMA) staining. Results. ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in α-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-β 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-β; 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 profibrogenic factors, and with the interstitial infiltration and myofibroblast activation. Conclusion. 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-β up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.
UR - http://www.scopus.com/inward/record.url?scp=17144458652&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.64.s86.8.x
DO - 10.1046/j.1523-1755.64.s86.8.x
M3 - Article
C2 - 12969126
AN - SCOPUS:17144458652
SN - 0098-6577
VL - 64
SP - S39-S45
JO - Kidney International, Supplement
JF - Kidney International, Supplement
IS - 86
ER -
