Genetic disruption of guanylyl cyclase/natriuretic peptide receptor‐A upregulates renal (pro)renin receptor expression in Npr1 null mutant mice

Abstract

Atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor‐a (GC‐A/NPRA), which regulates blood pressure through inhibition of renin‐angiotensin‐aldosterone system (RAAS). The aim of the present study was to determine whether targeted‐disruption of Npr1 (encoding GC‐A/NPRA) upregulates pro(renin) receptor (P)RR expression and leads to activation of MAPKs in Npr1 gene‐knockout mice. The Npr1 homozygous (Npr1−/−; 0‐copy), heterozygous (Npr1+/−; 1‐copy), wild‐type (Npr1+/+; 2‐copy), and gene‐duplicated homozygous (Npr1++/++; 4‐copy) mice were utilized. The renal expression of (P)RR, ACE‐1, and AT1R were analyzed. To identify the canonical pathway of (P)RR, we administered ACE‐1 inhibitor (captopril), AT1R inhibitor (losartan), and MAPKs inhibitors (U0126 and SB203580) to all Npr1 mice. The renal expression of (P)RR was increased by 3‐fold in 0‐copy and 2‐fold in 1‐copy mice compared with 2‐copy mice, which was also associated with increased expression of ACE‐1 and AT1R genes. Similarly, the renal expression of phosphorylated MAPKs (p‐Erk1/2 and p‐p38) were enhanced by 3.5‐fold and 3‐fold, respectively, in 0‐copy mice with significant increases in 1‐copy mice compared with 2‐copy mice. Proinflammatory cytokines were also significantly elevated in Npr1 0‐copy and 1‐copy mice. Treatment with captopril and losartan did not alter the expression of (P)RR in any of the Npr1 mice genotypes. Interestingly, losartan significantly reduced the expression of p‐ERK1/2 and p‐p38 in the Npr1 mice genotypes. The present findings suggest that ablation of Npr1 upregulates (P)RR, MAPKs (p‐Erk1/2 and p‐p38), and proinflammatory cytokines in 0‐copy and 1‐copy mice. In contrast, the duplication of Npr1 gene copy exhibited anti‐inflammatory and antihypertensive effects by reducing the expression of RAAS components, MAPKs, and proinflammatory cytokines.Support or Funding InformationThis work was supported by NIH grants (HL057531 and HL062147).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.