The renin-angiotensin system (RAS) may serve pathogenic as well as salutary roles in the development of renal disease, and angiotensin II has been implicated to regulate cellular mechanisms of fibrosis. To advance the understanding of the contribution of the RAS to the progression of renal disease, chronic obstructive nephropathy was studied in neonatal mice having 0, 1, 2 or 4 functional copies of the angiotensinogen gene (Agt) since: 1) all components of RAS are stimulated in obstructive nephropathy; and 2) these mice have genetically determined gradations in their steady-state plasma angiotensinogen levels. Two day-old mice underwent complete unilateral ureteral obstruction (UUO) or a sham operation (n=27 each). Obstructed (UUO), intact opposite (IO), and sham (S) kidneys were examined 28 d later for tubular atrophy and interstitial fibrosis, both hallmarks of chronic obstructive nephropathy. Sham and obstructed zero-copy mice exhibited a similar 20-30% reduction in body weight (P<0.05). In all genotypes, UUO induced a 40-80% reduction in renal mass compared to S, and IO demonstrated compensatory growth of 127-155% (both P<0.05). Compared to S, UUO increased tubular atrophy 100-fold in 1-4 copy mice. The elevated tubular atrophy in S of zero-copy mice was reduced in IO (both P<0.05). Interstitial collagen deposition, an index of fibrosis, increased in UUO linearly with Agt copy number, from 25.4 ± 9.6% in 0-copy mice to 54.2 ± 14.2% in 2-copy mice (R=0.723, slope=14.3 ± 3.3%, P<0.001), but fibrosis was not further elevated by UUO in 4-copy mice (58.5 ± 9.6%). Thus, in chronic neonatal UUO, less than normal levels of angiotensinogen decrease interstitial fibrosis. In contrast, tubular atrophy in the absence of Agt is prominent and not synergistic with UUO. We conclude: 1) Compensatory renal growth is independent of RAS activity; 2) Tubular integrity (measured by severity of tubular atrophy) is impaired in the absence of Atg; 3) Most importantly, this study demonstrates conclusively that the renal fibrotic response to chronic UUO is attenuated by decreasing angiotensinogen expression. It is likely that angiotensin-dependent fibrosis is a mechanism common to the progression of many forms of renal disease or injury.