Mineralocorticoid receptor blockade ameliorates nephropathy by increasing glucose-6-phosphate dehydrogenase activity and reducing oxidative stress in diabetic hypertensive rats

Author(s)

Bruno Sevá Pessôa

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2010-04-22

Examining board members

Jose Butori Lopes de Faria; Sílvia Maria de Oliveira Titan; Wilson Nadruz Junior

• Advisor: Jose Butori Lopes de Faria

Abstract

Strict glycemic management, control of blood pressure, and use of drugs that interfere with the renin angiotensin system are the most effective interventions for prevention and treatment of diabetic nephropathy. In addition, recent studies have suggested that beneficial effects of aldosterone blockade on diabetic nephropathy seem to be independent of blood pressure reduction and renin-angiotensin blockade on diabetic nephropathy. It has been demonstrated thah type 1 and type 2 diabetic animal models treated with aldosterone blocker had a beneficial effects in renal tissue through antioxidants and anti-inflammatory mechanisms. In vitro and in vivo studies showed a decreased in G6PD activity in high glucose and aldosterone levels leading to an increased in oxidative stress. In the present study we investigated whether spironolactone improves nephropathy by increasing G6PD activity and reducing oxidative stress in hypertensive diabetic rats. Spontaneously hypertensive rats were rendered diabetic by intravenous injection of streptozotocin. The diabetic animals were randomized to receive or not receive spironolactone for 8 weeks. Plasma glucose levels were higher in diabetic rats and it was not modified by spironolactone. Likewise, systolic blood pressure was unaltered by diabetes or by treatment. Albuminuria and renal expression of fibronectin were higher in the diabetic group compared to control, and these parameters were reduced with aldosterone blockade. G6PD activity and the GSH / GSSG ratio were reduced in diabetic rats and the treatment restored to control levels. Urinary levels of 8-OHdG and TBARS renal cortex levels, a marker of oxidative stress, were higher in diabetic rats when compared to controls, and the treatment reduced to control levels. The production of superoxide induced by NADPH oxidase and p47phox, an isoform of NADPH oxidase, was higher in diabetic rats when compared to controls and was signficantly reduced in treated rats. These results suggest that spironolactone ameliorates nephropathy in the diabetic hypertensive rats by restoring G6PD activity and diminishes oxidative stress without affecting blood pressure (AU)