A15395 Transgenic Rat Expressing the Human Chymase Gene as a Model of Human Hypertensive Disease

Abstract

Objectives: An incorrect knowledge of the primary angiotensin (Ang) II-forming enzyme and substrate in human cardiovascular organs continues to impede development of therapies with higher efficacy in suppressing intracrine Ang II actions. To circumvent this limitation, an experimental model harboring the human chymase (hCHY) and angiotensinogen genes are required. Toward this goal we describe the first transgenic rat model with whole body expression of the hCHY gene (hCHY Tg(+)). Methods: Initial characterization of 17–20 week old hCHY Tg(+) transgenic animals of both sexes (males = 9; females = 14) on the level of chymase mRNA and protein expression in hearts and kidneys as well as phenotypic changes are documented here. Sex- and age-matched wild type (WT) littermates (male = 6; females = 6) served as controls. Results: The presence of hCHY mRNA and protein was confirmed in hearts and kidneys of male and female transgenic animals while mRNA and protein of the transgene were not detected in the organs of WT controls. When compared to sex-matched WT littermates, systolic blood pressure recorded by telemetry was higher during both day- and night-time in male but not in female hCHY Tg(+) rats (Figure). While echocardiographic analysis of the left ventricular wall thickness and function showed no differences between WT and hCHY Tg(+) transgenic animals of both sexes, higher urinary protein excretion was observed in male (7.7 ± 1.8 vs 3.5 ± 1.3 mg/mg creatinine, p < 0.05) but not female hCHY Tg(+) rats (0.5 ± 0.04 vs 1 ± 0.3 mg/mg creatinine). Conclusion: Our study suggests that the in vivo expression of hCHY in transgenic rats is associated with hypertension and increased vascular permeability as reflected by the rise in urinary protein excretion in males.