Hyperaldosteronism and altered expression of an SGK1-dependent sodium transporter in ZDF rats leads to salt dependence of blood pressure

This study was designed to test whether altered aldosterone-related sodium handling leads to salt-sensitive blood pressure in diabetes and thus may exaggerate end-organ damage. Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes, and Zucker lean (ZL) rats, as euglycemic controls, were divided into groups receiving normal (0.28%) (ZDF+N, ZL+N) and high-salt (5.5%) diets (ZDF+S, ZL+S) for 10 weeks. Renal mRNA expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) and sodium transporters (for example, the epithelial sodium channel-α, ENaCα) were measured by quantitative reverse transcriptase-PCR. Vascular hypertrophy (media-to-lumen ratio, M/L) in mesenteric resistance arteries was assessed using a pressurized myograph. Systolic blood pressure (SBP) was significantly higher in ZDF+S vs . ZDF+N (146±2 vs . 133±3 mm Hg; P <0.05), whereas there was no difference between ZL+S and ZL+N (151±3 vs . 147±3 mm Hg). Plasma sodium concentration was higher in ZDF+S vs . ZDF+N, whereas there was no difference between ZL+S and ZL+N. Plasma aldosterone concentration (PAC) was higher in ZDF+N as compared with ZL+N (191±23 vs . 95±35 pg ml −1 ; P <0.05). PAC decreased to zero in ZL+S, which was not the case in ZDF+S (0±0 vs . 37±2 pg ml −1 ). Salt loading decreased the mRNA expression of SGK1 in euglycemic controls (ZL+S 0.58±0.2 vs . ZL+N 1.05±0.05; P =0.05), whereas it significantly increased SGK1 expression in diabetic rats (ZDF+S 1.75±0.15 vs . ZDF+N 0.92±0.07; P <0.01). ENaCα mRNA expression paralleled these changes. The M/L of mesenteric resistance arteries was not different between ZDF+N and ZL+N. High salt significantly increased the M/L in ZDF+S vs . ZDF+N, but not in ZL+S vs . ZL+N. Systolic blood pressure in this model of type 2 diabetes mellitus is salt sensitive, leading to marked vascular remodeling. The underlying pathophysiological mechanism may be inappropriately high levels of aldosterone and up-regulation of SGK1-dependent renal sodium transport by ENaCα, leading to net increased sodium retention.