Increased Urinary Angiotensinogen Reflects Intrarenal Renin-angiotensin System Activation in High Fat Diet Induced-type 2diabetic Mice

Obesity is a risk factor for diabetes mellitus (DM) and patients with DM are often hypertensive and exhibit inappropriate activation of the intrarenal renin-angiotensin system (RAS), which increases the risk for diabetic nephropathy and progression to chronic kidney disease. Enhanced intrarenal AGT levels contribute to increased intrarenal Angiotensin II levels. To examine the role of an activated RAS in DM, we measured urinary AGT along with albuminuria and other metabolic parameters in high fat diet induced-type 2 DM mice. Immediately after weaning, male C57BL/6J mice (N=18) were fed either a normal fat diet (18 % Kcal from fat; CT mice) or high fat diet (42.0 % Kcal from fat; HF mice) for 24 wk. Body weight (BW), food intake, and systolic blood pressure (SBP) by telemetry, were measured weekly. Glucose tolerance test (GTT) and homeostasis model assessment index of insulin resistance (HOMA-IR) were further assayed. At wks 0, 12, and 24 on dietary regimen, measurements of albuminuria and uAGT by ELISA were used as markers of renal injury and intrarenal RAS activation, respectively. Body weight increased by 140% in HF mice compared to 66 % in CT mice (from 18±0.5 to 44±1.4 g and 17±0.6 to 28±0.6 g, respectively) with no differences in daily energy intake (15.02±1.3 kcal/day and 15.4±0.8 kcal/day). Plasma glucose, area under curve (AUC) of GTT, and HOMA-IR were significantly increased in HF mice (121± 6mg/dL; 32,865±6,222; 5±1) compared to CT mice (220± 27mg/dL; 55,549±4,611; 54±9). In HF mice, SBP was augmented by wk 10 compared to CT mice (126±5 vs. 113±1 mmHg; P