First Author | Das S | Year | 2020 |
Journal | FASEB J | Volume | 34 |
Issue | 9 | Pages | 11925-11943 |
PubMed ID | 32686172 | Mgi Jnum | J:304186 |
Mgi Id | MGI:6694394 | Doi | 10.1096/fj.202000754R |
Citation | Das S, et al. (2020) Depletion of cyclic-GMP levels and inhibition of cGMP-dependent protein kinase activate p21(Cip1) /p27(Kip1) pathways and lead to renal fibrosis and dysfunction. FASEB J 34(9):11925-11943 |
abstractText | 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-alpha, IL-6) and pro-fibrotic (TGF-beta1) 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) . |