Gene targeting technology has produced mutant mice carrying selective null-mutation of the genes for the components of the renin-angiotensin system. Angiotensinogen null-mutant mice showed not only severe hypotension, but also several abnormal phenotypes in the kidney, including juxtaglomerular (JG) cell hypertrophy, renal arterial hypertrophy, and hypoplastic papilla. Although angiotensin type 1A (AT1A) receptor is by far the most predominant in mice, the phenotypes of AT1A null-deletion mice are much milder than those of angiotensinogen null-mutant mice. Because renin and angiotensin (ANG) production is upregulated in AT1A null-mutant mice, it is conceivable that the AT1B receptor provides compensation for the lost functions of AT1A. The observations in mice with complete absence of a gene product have not elucidated whether the abnormal phenotypes reflect direct effects caused by lack of local tissue action of ANG II or a secondary effect caused by changes in systemic milieu. We have developed chimeric mice that are made up of a mix of clusters of wild-type cells: cells homozygous for AT1A gene deletion. Within a given chimeric mouse, the expressions of renin mRNA and protein are identical between wild-type and mutant cells. In addition, all of the chimeric mice lack the renal arterial lesion observed in standard AT1A null-mutant mice. These findings indicate that both JG cell hypertrophy and renal vascular lesions are caused by systemic, rather than local, mechanism(s).