Abstract 374: Genetic Disruption of Guanylyl Cyclase/Natriuretic Peptide Receptor-AUpregulates Renal (Pro)Renin Receptor Gene Expression in Npr1 Mutant Mice

Abstract

Mice carrying targeted-disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene ( Npr1 ) exhibits hypertension, cardiac, and kidney hypertrophy, and congestive heart failure. The objective of the present study was to determine the role of (pro)renin receptor (P)RR in the kidneys of Npr1 gene-disrupted (-/-; 0-copy), and wild-type (+/+; 2-copy) mice. Disruption of Npr1 gene leads to increased systolic blood pressure by 36mmHg in 0-copy mice (138.4 ± 3.6) as compared with wild-type mice (102.2 ± 3.2 mm Hg). The renal (P)RR protein and mRNA levels were increased by 3-fold (4.8 ± 0.7 vs.1.3±0.4) and 3.5-fold (5.0 ± 0.5 vs.1.9 ± 0.3), respectively, in 0-copy mice compared with 2-copy control mice. To identify the Angiotensin II-independent mechanism of (P)RR, angiotensin converting enzyme (ACE) inhibitor, captopril and angiotensin II receptor-1 (AT1R) antagonist, losartan were administered to all Npr1 mice genotypes. The protein expression of ACE (3.9 ± 0.6 vs.1.9 ± 0.4; 2-fold) and AT1R (4.5 ± 0.4 vs.1.7; 2.5-fold) were decreased in 0-copy treated mice compared with 0-copy control mice, whereas the (P)RR expression was not altered by both inhibitors. Further, expression of phospho-extracellular regulated kinases (p-Erk1/2, 5.3 ± 0.7 vs 1.6 ± 0.5; 3-fold) and phospho-p38 (p-p38, 8.0 ± 0.8 vs. 2.1 ± 0.7; 4-fold) were increased in 0-copy mice as compared with 2-copy control mice. Treatment with Erk1/2 inhibitor U0126 and p38 inhibitor SB203580 attenuated the levels of p-Erk1/2 (6.8 ± 0.5 ± vs.1.1 ± 0.3; 6-fold) and p-p38 (4.7 ± 0.4 vs. 1.6 ± 0.5; 3-fold) in 0-copy treated mice as compared with 0-copy control mice. Captopril and losartan did not alter the expression levels of p-Erk1/2 and p-p38 in 0-copy mice as compared with 0-copy treated mice. The present results suggests that absence of NPRA/cGMP signaling causes increased expression of (P)RR and leads to MAPKs activation in the Npr1 null mutant mice.