Deletion of AT_1a receptors selectively in the proximal tubules of the kidney alters the hypotensive and natriuretic response to atrial natriuretic peptide via NPR_A/cGMP/NO signaling

In the proximal tubules of the kidney, angiotensin II (ANG II) binds and activates ANG II type 1 (AT_1a) receptors to stimulate proximal tubule Na⁺ reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates natriuretic peptide receptors (NPR_A) 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_1a and NPR_A receptors interact in the proximal tubules and whether natriuretic effects of NPR_A receptor activation by ANP may be potentiated by deletion of AT₁ (AT_1a) 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_1a receptors, PT-<i>Agtr1a</i>^-/-, to test the hypothesis that deletion of AT_1a receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower (<i>P</i> < 0.01), fractional proximal tubule Na⁺ reabsorption was significantly lower (<i>P</i> < 0.05), whereas 24-h urinary Na⁺ excretion was significantly higher, in PT-<i>Agtr1a</i>^-/- mice than in wild-type mice (<i>P</i> < 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-<i>Agtr1a</i>^-/- mice by inhibiting proximal tubule Na⁺ reabsorption compared with wild-type mice (<i>P</i> < 0.01). These augmented hypotensive and natriuretic responses to ANP in PT-<i>Agtr1a</i>^-/- mice were associated with increased plasma and kidney cGMP levels (<i>P</i> < 0.01), kidney cortical NPR_A and NPR_C mRNA expression (<i>P</i> < 0.05), endothelial nitric oxide (NO) synthase (eNOS) and phosphorylated eNOS proteins (<i>P</i> < 0.01), and urinary NO excretion (<i>P</i> < 0.01). Taken together, the results of the present study provide further evidence for important physiological roles of intratubular ANG II/AT_1a and ANP/NPR_A signaling pathways in the proximal tubules to regulate proximal tubule Na⁺ reabsorption and maintain blood pressure homeostasis.<b>NEW & NOTEWORTHY</b> This study used a mutant mouse model with proximal tubule-selective deletion of angiotensin II (ANG II) type 1 (AT_1a) receptors to study, for the first time, important interactions between ANG II/AT₁ (AT_1a) receptor/Na⁺/H⁺ exchanger 3 and atrial natriuretic peptide (ANP)/natriuretic peptide receptor (NPR_A)/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_1a and ANP/NPR_A signaling pathways in the regulation of proximal tubule Na⁺ reabsorption and blood pressure homeostasis.