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

Abstract

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 SD rats were administered either an empty retroviral vector (LNSV) or retroviral vector containing AT1 receptor antisense DNA (AT1R-AS). The virus (25 microl, 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 AT1R-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. AT1R-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 AT1R-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.

• Authors: M J Katovich, P Y Reaves, S C Francis, A S Pachori, H W Wang, M K Raizada
• Journal: Journal of hypertension (J Hypertens) Vol. 19 Issue 9 Pg. 1553-8 (Sep 2001) ISSN: 0263-6352 [Print] England
• PMID: 11564974 (Publication Type: Journal Article)

Chemical References

• Oligonucleotides, Antisense
• Receptor, Angiotensin, Type 1
• Receptors, Angiotensin
• Fructose

Topics

• Animals
• Blood Pressure
• Diet
• Fructose (administration & dosage)
• Genetic Therapy
• Glucose Intolerance (prevention & control)
• Hypertension (chemically induced, physiopathology, prevention & control)
• Insulin Resistance
• Male
• Oligonucleotides, Antisense (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Angiotensin, Type 1
• Receptors, Angiotensin (genetics)