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 mi ld hypertension and glucose intolerance. Although the mechanism of this glu cose 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 hyper tension 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 ant isense DNA (AT(1)R-AS). The virus (25 mul, 8 x 10(9) CFU/ml) was injected i nto 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% f ructose diet Indirect blood pressures (BP) were determined and an oral gluc ose tolerance test (OGTT) was performed when the animals had been on the re spective 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, fas ting blood glucose was comparable among the four groups; however, the gluco se excursion during the OGTT was significantly greater and more prolonged i n the LNSV-treated, fructose-fed group than the other three groups. AT(1)R- AS treatment significantly prevented glucose intolerance in the fructose ra t to levels observed in the controls. Conclusions Early fructose dietary treatment results in moderate hypertensi on and glucose intolerance, which is prevented by a single neonatal treatme nt with AT(1)R-AS. These results suggest that the RAS is involved in the gl ucose intolerance associated with fructose feeding and that genetic interve ntion is effective in this rat model. (C) 2001 Lippincott Williams& Wilkins .