Experimental gene manipulation for the renin-angiotensin and the kallikrein-kinin systems: impact on the understanding of cardiovascular regulation and genetic determinism of human diseases

The precise role of the different proteins that constitute the renin-angiotensin and kallikrein-kinin systems in the development of hypertension and some cardiac and renal diseases remains unclear. Genetic manipulations in animals is a powerful approach that provide the opportunity to explore the role of each of these proteins in vivo. Indeed it is possible in the rat and in the mouse to manipulate a specific gene without modifying the other genetic and environmental factors. A causal link can thus be established between the gene and a physiologic or pathologic alteration. The possibilities are either the overexpression of the gene in ail or in specific tissues (transgenesis), or the modification (often the inactivation) of the endogenous gene by homologous recombination. The second technique has the advantage to be more specific but it can be used only in the mouse; it is performed by transfecting totipotent embryonic stem cells with a vector harboring identical sequences to those of the gene to be targeted. The embryonic stem cells are then injected into embryos in which they will participate in the generation of the different organs including the gonads. The resulting chimeric animals can therefore transmit the mutation to their offspring creating a new genetically modified mouse strain. Many strains targeted in the different components of the renin-angiotensin and kallikrein-kinin systems have been generated in this way. These animal models should allow to test many physiopathological hypotheses that have been put forward from the results of human genetics and clinical studies, and also to raise new ones.