MURINE DOUBLE NULLIZYGOTES OF THE ANGIOTENSIN TYPE 1A AND 1B RECEPTORGENES DUPLICATE SEVERE ABNORMAL PHENOTYPES OF ANGIOTENSINOGEN NULLIZYGOTES

Rodents are the unique species carrying duplicated angiotensin (Ang) t ype 1 (AT1) receptor genes, Agtr1a and Agtr1b, After separately genera ting Agtr1a and Agtr1b null mutant mice by gene targeting, we produced double mutant mice homozygous for both Agtr1a and Agtr1b null mutatio n (Agtr1a-/-; Agtr1b-/-) by mating the single gene mutants. Agtr1a-/-, Agtr1b-/- mice are characterized by normal in utero survival but decr eased ex utero survival rate. After birth they are characterized by lo w body weight gain, marked hypotension, and abnormal kidney morphology including delayed maturity in glomerular growth, hypoplastic papilla, and renal arterial hypertrophy. These abnormal phenotypes are quantit atively similar to those found in mutant mice homozygous for the angio tensinogen gene (Agt-/-), indicating that major biological functions o f endogenous Ang elucidated by the abnormal phenotypes of Agt-/- are m ediated by the AT1 receptors. Infusion of Ang II, AT1 blockers, or an AT2 blocker was without effect on blood pressure in Agtr1a-/-; Agtr1b- /- mice, indicating that AT2 receptor does not exert acute depressor e ffects in these mice lacking AT1 receptors. Also, unlike Agt-/- mice, some Agtr1a-/-; Agtr1b-/- mice have a large ventricular septum defect, suggesting that another receptor such as AT2 is functionally activate d in Agtr1a-/-, Agtr1b-/- mice.