Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy

Renal angiotensin II up-regulation and myofibroblast activa- tion in human membranous nephropathy. Background. The molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely eluci- dated but the renin-angiotensin system (RAS) is involved. Idio- pathic 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 an- giotensin II (Ang II)) by immunohistochemistry. Transform- ing growth factor- (TGF-) and platelet-derived growth fac- tor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by -smooth muscle actin (-SMA) staining. Results. ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in -actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF- 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-; r 0.6, P 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expres- sion was associated with the tubular expression of these pro- fibrogenic factors, and with the interstitial infiltration and myo- fibroblast activation. Conclusion. Intrarenal RAS is selectively activated in pro- gressive MN. De novo expression of ACE at sites of tubulo- interstitial injury suggests that the in situ Ang II generation could participate in tubular TGF- up-regulation, epithelial- myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulo- interstitial injury.