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  • Title: Contribution of endothelin-1 to renal activator protein-1 activation and macrophage infiltration in aldosterone-induced hypertension.
    Author: Tostes RC, Touyz RM, He G, Chen X, Schiffrin EL.
    Journal: Clin Sci (Lond); 2002 Aug; 103 Suppl 48():25S-30S. PubMed ID: 12193048.
    Abstract:
    Aldosterone-induced hypertension is associated with renal damage that may be mediated by endothelin-1 (ET-1). We evaluated whether inflammatory cell infiltration and DNA-binding activity of the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) were increased in kidneys from aldosterone-infused rats. The role of ET-1 in these processes was evaluated by treating rats with the ET(A)-receptor blocker, BMS 182874. Rats were infused with aldosterone (0.75 microg/h) via a mini-osmotic pump and were given 1% NaCl in the drinking water in the absence and presence of BMS 182874 or of the aldosterone receptor blocker, spironolactone. Renal sections were used to assess inflammatory cell infiltration, which was identified immunocytochemically using monoclonal antibodies against macrophages (ED1+). Electrophoretic mobility shift assays evaluated the DNA-binding activity of NF-kappa B and AP-1 in renal tissue. Systolic blood pressure (BP) was increased in the aldosterone-infused group compared with controls (123+/-6 versus 110+/-10 mmHg, P<0.05). BMS 182874 and spironolactone significantly decreased BP (P<0.05). Macrophage infiltration was increased in the kidneys of aldosterone-infused rats compared with controls. Renal binding activity (arbitrary units) of AP-1, in contrast with that of NF-kappa B, increased in aldosterone-infused rats compared with control rats (AP-1, 4.2+/-0.3 versus 1.0+/-0.1, P<0.05; NF-kappa B, 1.6+/-0.5 versus 1.2+/-0.5). BMS 182874 and spironolactone decreased macrophage infiltration (by 70% and 50% respectively) and AP-1 binding activity (1.0+/-0.3 and 0.8+/-0.3 respectively). In conclusion, kidneys from aldosterone-infused rats exhibited macrophage infiltration and increased AP-1 DNA-binding activity. These processes were attenuated by BMS 182874. Our findings suggest that renal damage in aldosterone-dependent hypertension is associated with inflammatory processes that are mediated in part via ET-1.
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