RESUMEN

BACKGROUND: Studies implicate that angiotensin 1-7 (Ang1-7) imparts protective effects in the kidney. However, its relevance in hypertensive kidney disease is not fully understood. The purpose of this study was to explore the role of Ang1-7 on renal damage/remodeling during hypertension and its potential underlying molecular-cellular mechanisms. METHODS: Hypertension was induced in adult Sprague-Dawley rats by infusion of aldosterone (ALDO; 0.75 µg/hour) for 4 weeks with or without co-treatment of Ang1-7 (1 mg/kg/day). Untreated rats served as controls. Systolic blood pressure was monitored by tail-cuff technique. Renal fibrosis was evaluated by picrosirius red staining and renal collagen volume fraction was quantitated using imaging analyzing system. The expression of profibrotic factors [transforming growth factor-ß1 (TGF-ß1), platelet-derived growth factor-D (PDGF-D), fibroblast growth factor-1 (FGF-1), vascular endothelial growth factor-D (VEGF-D), and tissue inhibitors of metalloproteinases (TIMPs)] and free radical producing enzymes (inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in the kidney were examined by reverse transcription-polymerase chain reaction and western blot. Renal oxidative stress was assessed by malondialdehyde (MDA) measurement. RESULTS: Chronic ALDO infusion caused hypertension and hypertensive renal disease represented as glomerular damage/sclerosis. Ang1-7 co-treatment did not affect blood pressure in ALDO-treated rats, but significantly attenuated the glomerular damage/fibrosis. ALDO treatment significantly elevated renal expression of profibrogenic factors, including TGF-ß1, TIMP-1/TIMP-2, FGF-1, PDGF-D, and VEGF-D, whereas Ang1-7 co-treatment significantly reduced renal TGF-ß1, TIMP-1/TIMP-2, and FGF-1, but not PDGF-D and VEGF-D. Furthermore, ALDO infusion elevated NADPH oxidase (gp91phox) and MDA in the kidney, which was attenuated by Ang1-7 co-treatment. CONCLUSIONS: Ang1-7 plays a protective role in the hypertensive kidney disease independent of blood pressure. The beneficial effects of Ang1-7 are likely mediated via suppressing TGF-ß/FGF-1 pathways and oxidative stress.

Asunto(s)

Angiotensina I/farmacología , Hipertensión Renal/tratamiento farmacológico , Riñón/metabolismo , Nefritis/tratamiento farmacológico , Estrés Oxidativo , Fragmentos de Péptidos/farmacología , Animales , Antihipertensivos/farmacología , Presión Sanguínea/fisiología , Western Blotting , Modelos Animales de Enfermedad , Fibrosis/genética , Fibrosis/metabolismo , Fibrosis/patología , Regulación de la Expresión Génica , Hipertensión Renal/metabolismo , Hipertensión Renal/patología , Riñón/efectos de los fármacos , Riñón/patología , Linfocinas/biosíntesis , Linfocinas/genética , Masculino , Nefritis/metabolismo , Nefritis/patología , Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Factor de Crecimiento Derivado de Plaquetas/genética , ARN/genética , Ratas , Ratas Sprague-Dawley , Inhibidores Tisulares de Metaloproteinasas/biosíntesis , Inhibidores Tisulares de Metaloproteinasas/genética , Factor D de Crecimiento Endotelial Vascular/biosíntesis , Factor D de Crecimiento Endotelial Vascular/genética