Rescue of angiotensinogen-knockout mice

Angiotensinogen, the precursor of angiotensins I and II, is a critical comp onent of the renin-angiotensin system that plays an important role in regul ating blood pressure and electrolyte homeostasis. Genetically altered mice lacking angiotensinogen (Agt-KO) showed an expected phenotype, such as mark ed hypotension, but unexpected ones including abnormal kidney morphology, r educed survival rates of newborns, and impaired blood-brain barrier functio n after cold injury. To examine whether disruption of the angiotensinogen g ene is responsible for the observed phenotypes, we generated a line of mice heterozygous for the mouse angiotensinogen gene under the control of a mou se metallothionein-I promoter (MT-Agt) and crossmated transgenic mice with Agt-KO mice. The resulting mice (MT-Agt(+/-)/ Agt(-/-):MT-Agt/KO) produced the plasma level of angiotensin I comparable to that of wild-type mice, and the mutant phenotypes were rescued. These results indicated that the resul tant phenotypes due to the genetic deficiency of mouse angiotensinogen can be corrected by restoring angiotensinogen and angiotensin I in the circulat ion. (C) 1998 Academic Press.