Inhibition of renin-angiotensin-aldosterone system abolishes polymeric-IgA induced TGF- synthesis by human mesangial cells in IgA nephropathy

Abstract

The renin-angiotensin system (RAS) is involved in the development of progressive renal fibrosis in IgA nephropathy (IgAN). We had previously shown that polymeric IgA (pIgA) from IgAN patients up-regulated TGF-β synthesis by cultured human mesangial cells (HMC) through up-regulation of local RAS. In the present study, we examined the role of aldosterone (Aldo) in pIgA-induced TGF-β synthesis by HMC. Constitutive expression of the major components of renin-angiotensin-aldosterone system (RAAS) which regulate the synthesis and action of Aldo, including mineralocorticoid receptor (MR), 11β-hydroxysteroid dehydrogenase type II (11β-HSD2) and aldosterone synthesis (CYP11B2), was demonstrated in HMC by real-time PCR and immunofluorescence staining. Polymeric IgA were purified from IgAN patients (n=28) and normal subjects (n=24) using affinity and size exclusion chromatography. Aldo synthesis and CYP11B2 expression in HMC were up-regulated by pIgA from IgAN patient in dose- and time dependent manner, but not by pIgA from healthy subjects. Exogenous angiotensin II (AngII) significantly increased the expression of AngII receptor subtype-I (ATR1), CYP11B2 and Aldo synthesis by HMC. The release of TGF-β by HMC was up-regulated dose-dependently when HMC were incubated with either AngII or Aldo. Interesting, further increase in TGF-β release was observed when HMC were cultured with both AngII and Aldo. Addition of Aldo to HMC up-regulated the expression of angiotensin converting enzyme, angiotensinogen and the release of AngII. The data suggest the presence of a vicious cycle between pIgA-induced AngII and Aldo in HMC. Pre-incubation of HMC with either losartan or eplererone only partially suppressed the pIgA-induced TGF-β release (< 40%), while combination of both inhibitors achieved more than 90% inhibition of TGF-β release. In conclusion, our in vitro data suggest that aldosterone also plays an important role in the pIgA-induced TGF-β synthesis in HMC. Specific RAAS blockade with aldosterone in combination with ATR1 blocker could effectively ameliorate pIgA-induced mesangial injury in IgAN.