Improved Renal Function by Eta Receptor Blockade Is Associated with Reduced Renal Expression of Tgfβ and B FGF and Increased Activity of Mmp-2 in Shrsp

Abstract

P104 Endothelin-1 (ET-1) receptor antagonists increase life span and improve renal function in salt-loaded stroke prone SHR (SHRSP). Mechanisms underlying these ET-1-dependent processes are unclear. We hypothesized that ET-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male 8 week-old SHRSP (n=24) were randomized in 3 groups: control group; high salt diet (4% NaCl) and salt diet plus an ET A receptor antagonist, BMS 182874 (40 mg/Kg/day). Systolic blood pressure (SBP) was measured weekly and renal function assessed 2 weekly. After 20 weeks treatment, rats were killed. Expression of renal ET-1 and ET A /ET B receptor mRNA was evaluated by RT-PCR, renal expression of transforming growth factor β1 (TGF-β1) and basic fibroblast growth factor (bFGF) were determined by Western blot and, metalloproteinase (MMP-2) activity was measured by gelatine-enzymography. SBP increased to ∼ 240 mmHg in salt-loaded rats. BMS treatment had a small, but significant BP lowering effect and delayed progression and severity of renal dysfunction. In salt-loaded SHRSP renal ET-1 mRNA expression was increased (1.6±0.1vs control 1±0.1; p A receptor mRNA expression was decreased (0.7±0.1 vs control 1±0.1; p B subtype mRNA expression was unchanged. BMS treatment did not reverse these changes. Salt-loaded SHRSP exhibited increased renal expression of TGF-β1 (10.4±1SL-SHRSP vs 1±0.4 control, p A receptor blockade may be mediated, in part, by normalizing expression of growth factors and restoring MMP2 activity in experimental models of severe hypertension.