In the proximal tubules of the kidney, angiotensin II (ANG II) binds and activates ANG II type 1 (AT) receptors to stimulate proximal tubule Na reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates natriuretic peptide receptors (NPR) to inhibit ANG II-induced proximal tubule Na reabsorption. These two vasoactive systems play important counteracting roles to control Na reabsorption in the proximal tubules and help maintain blood pressure homeostasis. However, how AT and NPR receptors interact in the proximal tubules and whether natriuretic effects of NPR receptor activation by ANP may be potentiated by deletion of AT (AT) receptors selectively in the proximal tubules have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT receptors, PT-, to test the hypothesis that deletion of AT receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower ( < 0.01), fractional proximal tubule Na reabsorption was significantly lower ( < 0.05), whereas 24-h urinary Na excretion was significantly higher, in PT- mice than in wild-type mice ( < 0.01). Infusion of ANP via osmotic minipump for 2 wk (0.5 mg/kg/day ip) further significantly decreased blood pressure and increased the natriuretic response in PT- mice by inhibiting proximal tubule Na reabsorption compared with wild-type mice ( < 0.01). These augmented hypotensive and natriuretic responses to ANP in PT- mice were associated with increased plasma and kidney cGMP levels ( < 0.01), kidney cortical NPR and NPR mRNA expression ( < 0.05), endothelial nitric oxide (NO) synthase (eNOS) and phosphorylated eNOS proteins ( < 0.01), and urinary NO excretion ( < 0.01). Taken together, the results of the present study provide further evidence for important physiological roles of intratubular ANG II/AT and ANP/NPR signaling pathways in the proximal tubules to regulate proximal tubule Na reabsorption and maintain blood pressure homeostasis. This study used a mutant mouse model with proximal tubule-selective deletion of angiotensin II (ANG II) type 1 (AT) receptors to study, for the first time, important interactions between ANG II/AT (AT) receptor/Na/H exchanger 3 and atrial natriuretic peptide (ANP)/natriuretic peptide receptor (NPR)/cGMP/nitric oxide signaling pathways in the proximal tubules. The results of the present study provide further evidence for important physiological roles of proximal tubule ANG II/AT and ANP/NPR signaling pathways in the regulation of proximal tubule Na reabsorption and blood pressure homeostasis.