Mice deficient for angiotensinogen (AGT), or other components of the renin-angiotensin system, show a high rate of neonatal mortality correlated with severe renal abnormalities including hydronephrosis, hypertrophy of renal arteries, and an impaired ability to concentrate urine. Although transgenic replacement of systemic or adipose, but not renal, AGT in AGT-deficient mice has previously been reported to correct some of these renal abnormalities, the tissue target for this complementation has not been defined. In the current study, we have used a novel transgenic strategy to restore the peptide product of the renin-angiotensin system, angiotensin II, exclusively in the brain of AGTdeficient mice and demonstrate that brain-specific angiotensin II can correct the hydronephrosis and partially correct renal dysfunction seen in AGT-deficient mice. Taken together, these results suggest that the renin-angiotensin system affects renal development and function through systemically accessible targets in the brain.The renin-angiotensin system (RAS) 1 plays a critical role in the regulation of blood pressure and volume homeostasis in mammals. The main effector of the RAS is the octapeptide hormone angiotensin II (Ang II) produced by the successive enzymatic cleavage of the hepatic glycoprotein angiotensinogen (AGT) by kidney-derived renin and angiotensin-converting enzyme (ACE), a metalloprotease located at the surface of endothelial cells (1). Although Ang II acts through two receptors, type I and type II (AT1 and AT2, respectively), all of the known cardiovascular effects of Ang II are mediated by the AT1 receptor. In addition to this circulating RAS, the mRNA and protein for all of the RAS components have been identified in different tissues as brain, heart, adrenal gland, reproductive organs, and kidney (reviewed in Ref. 2), leading to the suggestion that tissue RAS (tRAS) might mediate cardiovascular and other functions within tissue sites.Inactivation of the RAS during development either by pharmacological inhibition or gene ablation also causes severe anomalies in the neonatal kidney, leading to hydronephrosis and impaired urine concentration (3). In humans, inhibition of the RAS during pregnancy is associated by a high rate of spontaneous abortion and in some strains of mice with a high rate of mortality in the first 3-5 weeks of life (4 -8).In an effort to understand the mechanisms that implicate the RAS in renal development, all of the genes coding for the components of the RAS from AGT to the angiotensin receptors have been disrupted in mice (9 -15). Although these results confirm that Ang II acting through the AT1 receptor is required for normal renal development, renal defects in mouse pups are only observed when both of the two AT1 isoforms present in mice (AT1A and AT1B (16 -18)) are inactivated, leading to the suggestion that each isoform can compensate in the absence of the other in the target tissue (19). Because only limited tissues, including the brain, adrenal gland, and testis, express both the AT1 re...