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. 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-beta up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.

Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy.

BACKGROUND: The molecular mechanisms of renal injury in diabetic nephropathy (DN) are not completely understood, although inflammatory cells play a key role. The renin-angiotensin system (RAS) is involved in kidney damage; however, few studies have examined the localization of RAS components in human DN. Our aim was to investigate in renal biopsies the expression of RAS and their correlation with proinflammatory parameters and renal injury. METHODS: The biopsies from 10 patients with type 2 diabetes mellitus and overt nephropathy were studied for the expression of RAS components by immunohistochemistry (IH). In addition, by Southwestern histochemistry we studied the in situ detection of the activated nuclear factor kappa B (NFkappaB), and by IH and/or in situ hybridization (ISH), the expression of monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES), whose genes are regulated by NFkappaB. RESULTS: Angiotensin-converting enzyme (ACE) immunostaining was elevated in tubular cells and appeared in interstitial cells. Elevated levels of angiotensin II (Ang II) immunostaining were observed in tubular and infiltrating interstitial cells. There was also a down-regulation of AT1 and up-regulation of AT2 receptors. An activation of NFkappaB and a marked up-regulation of NFkappaB-dependent chemokines mainly in tubular cells was observed. Elevated levels of NFkappaB, chemokines, and Ang II in tubules were correlated with proteinuria and interstitial cell infiltration. CONCLUSIONS: Our results show that in human DN, RAS components are modified in renal compartments, showing elevated local Ang II production, activation of tubular cells, and induction of proinflammatory parameters. These data suggest that Ang II contributes to the renal inflammatory process, and may explain the molecular mechanisms of the beneficial effect of RAS blockade.