| First Author | Periyasamy R | Year | 2019 |
| Journal | Peptides | Volume | 114 |
| Pages | 17-28 | PubMed ID | 30965084 |
| Mgi Jnum | J:291444 | Mgi Id | MGI:6443061 |
| Doi | 10.1016/j.peptides.2019.03.001 | Citation | Periyasamy R, et al. (2019) Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates renal (pro) renin receptor expression in Npr1 null mutant mice. Peptides 114:17-28 |
| abstractText | The objective of the present study was to determine whether targeted-disruption of Npr1 gene (encoding for guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) upregulates pro(renin) receptor (P)RR expression and leads to the 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 (Npr1(++/++); 4-copy) mice were utilized. To identify the canonical pathway of (P)RR, we administered ACE-1 inhibitor (captopril), AT1R blocker (losartan), and MAPKs inhibitors (U0126 and SB203580) to all Npr1 mice genotypes. The renal expression of (P)RR mRNA was increased by 3-fold in 0-copy mice and 2-fold in 1-copy mice compared with 2-copy mice, which was also associated with significantly increased expression of ACE-1 and AT1R mRNA levels. Similarly, the phosphorylation of MAPKs (Erk1/2 and p-p38) was enhanced by 3.5-fold and 3.2-fold, respectively, in 0-copy mice with significant increases in 1-copy mice compared with 2-copy mice. The kidney and plasma levels of proinflammatory cytokines were significantly elevated in 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 phosphorylation of Erk1/2 and p38 in Npr1 mice. The present results suggest that the ablation of Npr1 upregulates (P)RR, MAPKs (Erk1/2 and p38), and proinflammatory cytokines in 0-copy and 1-copy mice. In contrast, the duplication of Npr1 exhibits the anti-inflammatory and antihypertensive effects by reducing the activation of MAPKs and inhibiting the expression levels of RAAS components and proinflammatory cytokines. |
