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Dynamic changes of the renin-angiotensin and associated systems in the rat after pharmacological and dietary interventions in vivo

Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan

To address the multiplicity of the renin-angiotensin system (RAS) with particular interest in its local, synergistic regulation, we investigate dynamic changes of the RAS and associated systems in response to external stimuli in the rat. We tested influences of the RAS blockade (candesartan and enalapril), diuretics (hydrochlorothiazide), high lipid diet, and salt loading on tissue mRNA level of 12 principal genes. Under the hemodynamic conditions appropriately predetermined, we quantitatively evaluated mRNA level changes with and without each intervention in five organs–the brain, heart, kidney, liver, and adipose tissues–of male rats (n = 5 each). A total of 250 tissues were examined by real-time PCR. Significant changes in mRNA level (P < 0.05) were found in a drug-, diet- and tissue-specific manner. For instance, 29% of genes (14 out of 48 tissues showing detectable mRNA levels) were differentially regulated by candesartan and enalapril, although both drugs reduced blood pressure to similar extents. When the overall interactions among 12 genes were compared between interventions, the RAS and associated systems appeared to change in the opposite direction between candesartan and high lipid diet in the adipose tissue and between candesartan and salt loading in the heart. Enalapril, however, induced unique patterns of perturbation in the local RAS under the corresponding conditions. Thus, this study provides a fundamental picture of gene expression profile in vivo in the RAS and associated systems. In particular, our data highlight differential regulation between candesartan and enalapril, which may reflect the individual pharmacological properties regarding clinical implications.

renin-angiotensin system; mRNA; gene expression; diuretics; diet