Binding of atrial natriuretic peptide (ANP) to its guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) exerts diverse physiological effects by lowering the blood pressure and blood volume. The objective of the present study was to determine the effect of blockade of nuclear factor-kappa B, inhibitory kappa B kinase, and inhibitory kappa B alpha (NF-κB, IKK, IκBα) in the kidneys of
Npr1
(coding for GC-A/NPRA) gene-disrupted mice. The disruption of
Npr1
greatly
stimulated the renal NF-κB binding activity by 6-fold (57.12 ± 3.35 vs 9.42 ± 0.92), IKK activity by 8-fold (56.05 ± 3.83 vs 6.85 ± 0.90), and IκBα phosphorylation by 11-fold (46.67 ± 1.32 vs 4.15 ±0.58), respectively, in the kidneys of null mutant (-/-; 0-copy) mice as compared with wild-type (+/+; 2-copy) mice. Interestingly, the expression levels of IκBα were reduced by 80% (5.35 ± 0.58 vs 31.64 ± 1.13) and pro-inflammatory cytokines and renal fibrosis were enhanced by 6- to 8-fold and 5-fold (32.58 ±2.06 vs 5.85 ± 0.91), respectively, in 0-copy mice than 2-copy mice. However, the treatment of 0-copy mice with NF-κB inhibitors, andrographolide, pyrrolidine dithiocarbamate, and etanercept showed a substantial reduction in renal fibrosis by 50% (14.09 ± 2.13, 18.01 ± 1.69, and 15.88 ± 0.70, respectively), attenuation of pro-inflammatory cytokines gene expression by 60-65%, IKK activity by 60% (25.37 ± 2.22, 22.67 ± 2.23, and 19.21 ± 2.50), and IkBα phosphorylation by 65-70% (19.68 ± 1.35, 24.67 ± 1.44, 16.62 ± 1.42), respectively. Our findings demonstrate that the disruption of
Npr1
activates NF-κB activity, expression of various pro-inflammatory cytokines, and renal fibrosis in 0-copy mice. However, the treatments with NF-kB inhibitors suppress NF-kB activity and pro-inflammatory cytokines and repairs the fibrosis in the kidneys of
Npr1
null mutant mice. The present results suggest that the blockade of NF-kB activity provides protective effects against the inflammatory and fibrotic responses in the kidney.
Interferon regulatory factor 5 and nuclear factor kappa‐B exhibit cooperating but also divergent roles in the regulation of pro‐inflammatory cytokines important for the development of
TH
1 and
TH
17 responses
