TARGETED INACTIVATION OF THE REN-2 GENE IN MICE

Several recent studies have demonstrated that ablation of genes of the renin-angiotensin system can have wide-ranging and sometimes unexpect ed effects. Renin is directly involved in blood pressure regulation an d is encoded by a single gene in most mammals. Wild mouse strains and some inbred laboratory strains have a duplicated renin gene (Ren-2), t he physiological significance of which is unclear. Significant differe nces exist in the structure and expression of these renin genes, but a s yet, no distinct biological function that distinguishes these genes has been defined. We have used gene targeting to discover the effects of inactivating the duplicated (Ren-2) gene in strain 129 mice, and we show that mice lacking the Ren-2 gene are viable and healthy. There a ppear to be no histopathological differences in renin-expressing tissu es between Ren-2-null mice and their controls. Studies of our Ren-2-nu ll mice allow, for the first time, a direct evaluation of the ability of the Ren-1(d) gene to regulate blood pressure in the absence of expr ession of the Ren-2 enzyme. We observed no alteration to blood pressur e in adult mice homozygous for the mutated Ren-2 gene, even though the concentration of active renin is increased and of prorenin is decreas ed in plasma of these mice. Ren-1(d) is therefore capable of regulatin g normal blood pressure and despite a different tissue expression prof ile, is functionally equivalent to Ren-1(c).