Proximal Tubule‐Specific Deletion of Angiotensin II Type 1a Receptors Augments Natriuretic Response to Atrial Natriuretic Peptide via NPRA/cGMP/NO Signaling Pathways in the Kidney

Abstract

We and others have previously shown that the proximal tubules of the kidney expressed high levels of angiotensin II (Ang II) type 1 (AT1) receptors and atrial natriuretic peptide (ANP) type A receptors (NPRA). In the proximal tubules, Ang II binds and activate AT1 (AT1a) receptors to stimulate proximal tubule Na+reabsorption, whereas ANP binds and activates NPRA receptors to inhibit Ang II‐induced proximal tubule Na+reabsorption. Interactions between Ang II and ANP systems play important counteracting roles in the proximal tubules to control proximal tubule Na+ reabsorption in the kidney and maintain blood pressure homeostasis. It is not known, however, whether the hypotensive and natriuretic responses to ANP are altered by the absence of AT1 (AT1a) receptor‐mediated antinatriuretic action of Ang II in the proximal tubules. The present study used a novel mouse model with proximal tubule‐specific knockout of AT1a receptors in the kidney, PT‐Agtr1a−/−, to test the hypothesis that deletion of AT1a receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Two groups (n=9‐12 per group) of adult male wild‐type and PT‐Agtr1a−/− mice were infused without (time controls) or with ANP via osmotic minipump (10 ng/min, i.p.) continuously for 2 weeks. Basal blood pressure was about 16 ± 3 mmHg lower (P<0.01), fractional proximal tubule Na+ reabsorption was lower (P<0.05), and 24 h urinary Na+ excretion was higher in PT‐Agtr1a−/− mice (P<0.01), compared with wild‐type mice. ANP infusion decreased blood pressure and increased the natriuretic response in PT‐Agtr1a−/− mice further by inhibiting proximal tubule Na+ reabsorption, compared with wild‐type controls (P<0.01). The augmented hypotensive and natriuretic responses to ANP infusion in PT‐Agtr1a−/− mice was associated with increased plasma and kidney cGMP levels (P<0.01), kidney NPRA and NPRC expression (P<0.05), total eNOS and phosphorylated eNOS proteins (P<0.01), and urinary NO excretion (P<0.01), respectively. Taken together, the results of the present study provide further new insights into the important physiological roles for intratubular Ang II/AT1a and ANP/NPRA in the proximal tubules to regulate proximal tubule Na+ reabsorption and help maintain blood pressure homeostasis.