Sexual Dimorphism in Renal Heme-Heme Oxygenase System in the Streptozotocin Diabetic Rats

Barbara      Bonacasa; Cayetano      Perez; Miguel      G. Salom; Bernardo      Lopez; Fara      Saez-Belmonte; Pedro      Martinez; Teresa      Casas; Francisco      J. Fenoy; Francisca      Rodriguez

doi:10.2174/1381612811319150002

Abstract

Heme Oxygenase (HO) –1 and –2 exert antioxidant, cytoprotective and vascular actions in male diabetic rats. However, there is no information about the expression and functional significance of the renal HO system in diabetic females. The present study tested the hypothesis that the HO system is differentially regulated in the kidney of female Sprague Dawley diabetic rats, protecting it from nitrosative and glomerular functional damage. Two weeks after the administration of streptozotocin (STZ; 65 mg/kg. i.p), males (DM) and females (DF) showed hyperglycemia, polyuria and elevated kidney/body weight ratio, compared to their control males (CM) and females (CF). In conscious animals, creatinine clearance was higher (0.5±00 vs. 0.3±00; ml/min/100g BW; p<0.05) and urinary albumin excretion was lower (0.7±0.3 vs 3.1±0.7; mg/day) in DF compared to DM. Acute administration of a HO inhibitor stannous mesoporphyrin (SnMP 40 mol/kg, i.v.) induced a greater renal vasoconstrictor response in DF than in DM. Western blot analysis of renal tissue revealed higher renal cortex HO-1 protein levels in DF compared to all other groups; by immunohistochemistry this induction of HO-1 in DF was localized in tubular segments and glomeruli. Furthermore, renal cortical concentration of nitrosylated protein was higher in DM than in DF animals and inversely related with HO-1 levels in both renal cortex and medulla. These data demonstrate that the HO-1 protein is induced in females, associated with renal vasodilation, decreased renal nitrosative stress and reduced albuminuria, indicating that the HO system is protecting the kidney from diabetes-induced damage specifically in females.

Keywords: Gender, type-1 diabetes, heme oxygenase, oxidative stress

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