Depletion of cyclic-GMP levels and inhibition of cGMP-dependent protein kinase activate p21 /p27 pathways and lead to renal fibrosis and dysfunction.

Cell-cycle regulatory proteins (p21 /p27 ) inhibit cyclin and cyclin-dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21 /p27 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.