Oxidative Stress in a Rat Model of Obesity-Induced Hypertension

Abstract

45 The mechanisms underlying the development of hypertension in obesity are not yet fully understood. We recently reported the development of hypertension in a rat model of diet-induced obesity (Dobrian AD et al Hypertension 2000;35: in press). When Sprague-Dawley rats (n=60) are fed a moderately high fat diet(32kcal% fat) for 10-16 weeks, about half of them develop obesity (obesity-prone (OP) and mild hypertension (153±3.4 mmHg systolic pressure), whereas the other half (obesity-resistant, OR) maintains body weight equivalent to low fat control (C) and are normotensive. We examined the potential role of oxidative stress in the development of hypertension in this model. Lipid peroxides measured as thiobarbituric acid reactive substances (TBARS) are showing a significant increase in the LDL fraction of OP rats (2.8±0.32 nmol MDA/mg protein) compared to OR and C (0.9±0.3 nmol MDA/mg protein). Also, aortic and kidney TBARS showed a significant 3- and 5- fold increase in OP rats after 16 weeks of diet (3.3±0.44 aorta and 6.7±0.52 nmol MDA/mg protein kidney) vs OR. In addition, superoxide generation by aortic rings, measured by lucigenin (25μM) luminescence showed a 2-fold increase in the OP group (4325.6±174 RLU/15 min/mg DNA X10 5 ) compared to both OR and C. Plasma renin activity was 2-fold increased in OP vs both OR and control groups.The urine nitrate/nitrite measured by LDH colorimetric method showed a 1.8-fold decrease in OP rats (2.4±0.17 μmoles) compared to OR. A similar 1.6-fold decrease was found for plasma nitrate/nitrite in OP rats vs OR and C. However, eNOS expression assessed by semiquantitative RT-PCR showed a strong increase in the OP rats vs OR and controls in both kidney cortex(eNOS/β-actin ratio of 0.78±0.21 in OP vs 0.32±0.16 in OR)and medulla(0.86±0.18 in OP vs 0.36±0.14 in OR), suggesting a possible shift toward superoxide vs NO production by the eNOS enzyme.Also, eNOS expression was increased ∼4.8-fold in the thoracic aorta of OP compared to OR rats. Collectively, data show a decreased NO production in OP animals, due in part to the increased oxidative stress, possibly generated by the activation of renin-angiotensin system and increased eNOS expression.