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

Abstract

Cell‐cycle regulatory proteins (p21Cip1/p27Kip1) inhibit cyclin and cyclin‐dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21Cip1/p27Kip1 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, p21Cip1, and p27Kip1 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 p21Cip1 and p27Kip1.

Oct4-dependent FoxC1 Activation Improves the Survival and Neovascularization of Mesenchymal Stem Cells under Myocardial Ischemia

“…These growth factors are key in survival and angiogenesis of MSCs [50,52]. But, in contrast, Oct4 deletion resulted in increased expression of proin ammatory (IL6) and pro-brotic (TGFβ1) cytokines critically involved in brosis [11]. This change is correlated with reduced MEndoT and increased brosis in MSCs under hypoxia.…”

Oct4-dependent FoxC1 activation improves the survival and neovascularization of mesenchymal stem cells under myocardial ischemia

“…These growth factors are key in survival and angiogenesis of MSCs [ 53 , 55 ]. But, in contrast, Oct4 deletion resulted in increased expression of pro-inflammatory (IL6) and pro-fibrotic (TGFβ1) cytokines critically involved in fibrosis [ 12 ]. This change is correlated with reduced MEndoT and increased fibrosis in MSCs under hypoxia.…”

Knockdown of hsa_circ_0001275 reverses dexamethasone-induced osteoblast growth inhibition via mediation of miR-377/CDKN1B axis

“…CDKN1B (p27 Kip1) was targeted by miR-377. CDKN1B has been reported to regulate G 1 progression and maintain the cell function in response to cell proliferation inhibition or cell differentiation [36,37]. In addition, it has been confirmed that CDKN1B can act as a key modulator in cell growth by induction of CDK2 and Cyclin E1 [38,39].…”