Cell‐cycle regulatory proteins (p21 ^Cip1 /p27 ^Kip1 ) inhibit cyclin and cyclin‐dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21 ^Cip1 /p27 ^Kip1 in the progression of renal fibrosis and dysfunction using Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor‐A, GC‐A/NPRA) gene‐knockout (0‐copy; Npr1 ^−/− ), 2‐copy ( Npr1 ^+/+ ), and 4‐copy ( Npr1 ^++/++ ) mice treated with GC inhibitor, A71915 and cGMP‐dependent protein kinase (cGK) inhibitor, (Rp‐8‐Br‐cGMPS). A significant decrease in renal cGMP levels and cGK activity was observed in 0‐copy mice and A71915‐ and Rp‐treated 2‐copy and 4‐copy mice compared with controls. An increased phosphorylation of Erk1/2, p38, p21 ^Cip1 , and p27 ^Kip1 occurred in 0‐copy and A71915‐treated 2‐copy and 4‐copy mice, while Rp treatment caused minimal changes than controls. Pro‐inflammatory (TNF‐α, IL‐6) and pro‐fibrotic (TGF‐β1) cytokines were significantly increased in plasma and kidneys of 0‐copy and A71915‐treated 2‐copy mice, but to lesser extent in 4‐copy mice. Progressive renal pathologies, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were observed in 0‐copy and A71915‐treated 2‐copy and 4‐copy mice, but minimally occurred in Rp‐treated mice compared with controls. These results indicate that Npr1 has pivotal roles in inhibiting renal fibrosis and hypertrophy and exerts protective effects involving cGMP/cGK axis by repressing CDK blockers p21 ^Cip1 and p27 ^Kip1 .

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