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
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 ETA 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 ETA/ETB 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<0.05), and ETA receptor mRNA expression was decreased (0.7±0.1 vs control 1±0.1; p<0.05). ETB 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<0.05) but not of bFGF (1.2±0.1 vs control 1±0.02) and augmented activity of MMP-2 (4.8±1.6 vs control 1±0.3, p<0.05). Treatment with BMS decreased expression of both TGF-β1 (6±0.4, p<0.05) and bFGF (0.6±0.1, p<0.05), and reduced MMP-2 activity (0.3±0.1). These data suggest that severe hypertension and renal dysfunction in salt-loaded SHRSP is associated with increased expression of renal ET-1 and growth factors. These effects were ameliorated by BMS treatment. In conclusion, nephroprotection by ETA receptor blockade may be mediated, in part, by normalizing expression of growth factors and restoring MMP2 activity in experimental models of severe hypertension.