Deletion of AT1a receptors selectively in the proximal tubules alters the hypotensive and natriuretic response to ANP via NPRA/cGMP/NO Signaling.

In the kidney, vasoactive peptide hormones angiotensin II (Ang II), via AT_1a receptors, and atrial natriuretic peptide (ANP), via NPR_A receptors, reportedly play counteracting roles to regulate proximal tubule Na⁺ reabsorption and maintain blood pressure homeostasis. However, how AT_1a and NPR_A receptors interact in the proximal tubules and whether deletion of AT₁ (AT_1a) receptors selectively in the proximal tubules alters the hypotensive and natriuretic effects of ANP) have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT_1a receptors 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, fractional proximal tubule Na⁺ reabsorption was significantly lower, whereas 24 h urinary Na⁺ excretion was significantly higher in PT-Agtr1a^-/- than in wild-type mice (P<0.01). Infusion of ANP for 2 weeks (0.5 mg/kg/day, i.p.) further significantly decreased blood pressure and increased the natriuretic response in PT-Agtr1a^-/- mice by inhibiting proximal tubule Na⁺ reabsorption (P<0.01). These augmented hypotensive and natriuretic responses to ANP in PT-Agtr1a^-/- mice were associated with increased plasma and kidney cGMP levels (P<0.01), kidney cortical NPR_A and NPR_C mRNA expression (P<0.01), total and phosphorylated endothelial nitric oxide synthase (eNOS) (P<0.01), and urinary nitric oxide (NO) excretion (P<0.01). Taken together, the results of the present study support important physiological roles of Ang II/AT_1a and ANP/NPR_A signaling pathways in the proximal tubules to regulate proximal tubule reabsorption and maintain blood pressure homeostasis.