Enhanced expression of pro‐renin receptor and proinflammatory cytokines in Npr1 gene disrupted 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 present study was aimed to determine whether targeted‐disruption of Npr1 gene (coding for GC‐A/NPRA) upregulates pro(renin) receptor (P)RR expression and leads to activation of mitogen activated protein kinases (MAPKs) in Npr1 gene‐knockout mice. The results showed that Npr1 gene disruption enhanced renal (pro)renin receptor expression by 3‐fold in 0‐copy (−/−) mice compared with 2‐copy (+/+) control mice, which in turn was associated with increased expression of angiotensin converting enzyme (ACE) and angiotensin receptor type 1 (AT1R) gene by 2‐fold and 3‐fold respectively. To identify the angiotensin II‐ (Ang II) dependent and ‐independent mechanism of (P)RR, ACE inhibitor captopril and AT1R antagonist losartan were administered to Npr1 mice genotypes. Both drugs did not alter the expression of (pro)renin receptor in all Npr1 mice genotypes. In parallel, renal expression of (MAPKs) p‐Erk1/2 and p‐p‐38 were increased by 2.5‐fold and 3‐fold in 0‐copy mice compared with 2‐copy control mice. Treatment with captopril did not alter the expression of p‐Erk1/2 and p‐p38 in Npr1 mice genotypes compared with their untreated mice counterparts. Interestingly, losartan reduced the expression of p‐ERK1/2 and p‐p38 in 1‐copy mice compared with vehicle‐treated control groups. The present findings suggest that disruption of Npr1 gene upregulates (P)RR and activates MAPKs p‐Erk1/2 and p‐p38 in 0‐copy mice, independent of Ang II generation by enhancing pro‐inflammatory cytokines in a gene dose‐dependent manner.Support or Funding InformationNIH/NHLBI: HL57531NIH/NHLBI: HL62147This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.