Published Online
on October 20, 2003

A more recent version of this article appeared on November 1, 2003

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Submitted on May 30, 2003
Revised on June 9, 2003

Gene Therapy With Human Tissue Kallikrein Reduces Hypertension and Hyperinsulinemia in Fructose-Induced Hypertensive Rats

Chunxia Zhao; Peihua Wang; Xiao Xiao; Julie Chao; Lee Chao; Dao Wen Wang^*; and Darryl C. Zeldin

From the Cardiovascular Division of Internal Medicine, Department and Gene Therapy Center, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology (C.Z., P.W., X.X., D.W.W.), Wuhan, Peoples Republic of China; the Department of Biochemistry, Medical University of South Carolina (J.C., L.C.), Charleston; and the Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health (D.C.Z.), Research Triangle Park, NC.

^* To whom correspondence should be addressed. E-mail: dwwang{at}tjh.tjmu.edu.cn.

Abstract--This study investigates gene therapy with human tissue kallikrein as a treatment for fructose-induced hypertension in rats. Hypertension was induced by addition of 10% fructose to drinking water. Fructose-fed rats also had increased serum insulin and triglycerides, decreased urine osmolarity, increased urine volume and endothelin-1, and increased aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels. Fructose-induced hypertensive and control rats were injected intravenously with a construct containing the human tissue kallikrein cDNA. Two weeks after injection of hypertensive rats, systolic blood pressure and serum insulin levels normalized, urine osmolarity increased, urine endothelin-1 levels decreased, and aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels decreased. In contrast, injection of the human tissue kallikrein cDNA had minimal effect on blood pressure or insulin levels in control rats. These results suggest that gene therapy with human tissue kallikrein may have potential as a treatment for hypertension and associated insulin resistance. Moreover, our data suggest that the beneficial effects of human tissue kallikrein on these parameters are associated with changes in endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 expression.

Key words: kinins • diabetes mellitus • hypertension, renal • endothelin • receptors, endothelin • angiotensin II

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