Gene therapy attenuates the elevated blood pressure and glucose intolerance in an insulin-resistant model of hypertension

Objective Fructose feeding in male Sprague-Dawley (SD) rats results in a mild hypertension and glucose intolerance. Although the mechanism of this glucose intolerance and hypertension is not completely understood, a role for the renin-angiotensin system (RAS) has been proposed. In the current study our aim was to test the hypothesis that intervention of the RAS with a gene therapy approach would be effective in preventing the development of hypertension and glucose intolerance in this animal model. Design and methods Five-day-old SID rats were administered either an empty retroviral vector (LNSV) or retroviral vector containing AT(1) receptor antisense DNA (AT(1)R-AS). The virus (25 mul, 8 x 10(9) CFU/ml) was injected into the heart and the animals were returned to their mothers. After weaning, half the animals from each group were placed on breeder's chow or a 60% fructose diet Indirect blood pressures (BP) were determined and an oral glucose tolerance test (OGTT) was performed when the animals had been on the respective diets for 2 months. Results Fructose-fed animals developed mild hypertension (145 +/- 3 versus 132 +/- 4 mmHg) by 6 weeks of dietary intervention. This increase in BP was prevented by AT(1)R-AS treatment (125 +/- 3 mmHg). At 2 months of age, fasting blood glucose was comparable among the four groups; however, the glucose excursion during the OGTT was significantly greater and more prolonged in the LNSV-treated, fructose-fed group than the other three groups. AT(1)R-AS treatment significantly prevented glucose intolerance in the fructose rat to levels observed in the controls. Conclusions Early fructose dietary treatment results in moderate hypertension and glucose intolerance, which is prevented by a single neonatal treatment with AT(1)R-AS. These results suggest that the RAS is involved in the glucose intolerance associated with fructose feeding and that genetic intervention is effective in this rat model. (C) 2001 Lippincott Williams& Wilkins.