Molecular and Cellular Effect of Angiotensin 1-7 on Hypertensive Kidney Disease.

Background: Studies implicate that Ang1-7 imparts protective effects in the kidney. However, its relevance in hypertensive kidney disease is not fully understood. The purpose of this study is 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 ALDO (0.75μg/h) for 4 weeks with or without co-treatment of Ang1-7 (1mg/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 CVF was quantitated using imaging analyzing system. The expression of profibrotic factors (TGF-β1, PDGF-D, FGF-1, VEGF-D and TIMPs) and free radical producing enzymes (iNOS and NADPH oxidase) in the kidney were examined by RT-PCR and Western blot. Renal oxidative stress was assessed by 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-β1, TIMP-1/TIMP-2, FGF-1, PDGF-D and VEGF-D, while Ang1-7 co-treatment significantly reduced renal TGF-β1, 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-β/FGF-1 pathways and oxidative stress.