Disruption of Guanylyl Cyclase‐A/Natriuretic Peptide Receptor‐A Gene Leads to an Increased Synthesis of Pro‐inflammatory Cytokines and Fibrosis in the Kidney.

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The objective of the present study was to evaluate the effect of Npr1 (coding for Guanylyl Cyclase‐A/Natriuretic Peptide Receptor‐A; GC‐A/NPRA) gene‐disruption in the development of renal hypertrophy and fibrosis. Blood pressure measurement and plasma cytokine assays were performed in 16‐weeks old mice having different copies of Npr1 gene (0‐copy, 1‐copy and 2‐copy). The 0‐copy mice showed 35‐45 mmHg higher systolic blood pressure (SBP) as compared with 2‐copy mice. A significant increase in plasma levels of tumor necrosis factor (TNF‐α; 5‐fold) and interleukin‐6 (IL‐6; 2.5‐fold) were observed in 0‐copy mice as compared with 2‐copy mice. Moreover, protein analysis also showed a significant increased expression levels of transforming growth factor (TGF‐β) and reduced expression of matrix metalloproteinases (MMP's) by Western blot analysis in 0‐copy mice as compared with 2‐copy wild‐type mice. Renal collagen content was significantly increased by 2‐fold in 0‐copy mice and was confirmed by histological study with masson's trichrome staining of kidney tissues. The increased levels of TNF‐α, IL‐6, and TGF‐β as well as a reduced levels of MMP's in 0‐copy mice indicated the ensuing process of renal fibrosis in these animals. Thus, the present results suggest that the absence of ANP/NPRA signaling exerts a stimulatory effect to cause significant increase in pro‐inflammatory cytokines to produce hypertrophy and fibrosis in the kidney.