C‐peptide prevents NF‐κB from recruiting p300 and binding to the inos promoter in diabetic nephropathy

Abstract

C-peptide (CP) has demonstrated unique beneficial effects in diabetic nephropathy (DN), but whether and how CP regulates NF-κB and its coactivator, p300, to suppress inducible iNOS and antagonize DN are unknown. iNOS expression, NF-κB nuclear translocation, colocalization and binding of NF-κB to p300, binding of NF-κB to the inos promoter, and the bound NF-κB, p300, and histone 3 lysine 9 acetylation (H3K9ac) at binding sites were measured in high glucose-stimulated mesangial cells. We evaluated pathologic changes, iNOS expression, NF-κB, and p300 contents in diabetic rats. We found that CP inhibited iNOS expression and notably prevented colocalization and binding of NF-κB and p300. CP prevented NF-κB from binding to the inos promoter, especially at the distal site, and reduced bound NF-κB, p300, and H3K9ac. N-terminal plus middle fragment could mostly mimic the antagonizing effects of CP against the pathologic changes of DN and equally suppresses renal iNOS expression as CP. In conclusion, CP prevented NF-κB from recruiting p300 and binding to the inos promoter, and decreased H3K9ac at the binding sites to suppress iNOS expression and antagonize DN, with the effect region identified as N-terminal plus middle fragment.-Li, Y., Li, X., He, K., Li, B., Liu, K., Qi, J., Wang, H., Wang, Y., Luo, W. C-peptide prevents NF-κB from recruiting p300 and binding to the inos promoter in diabetic nephropathy.

Enhancer RNA and NFκB-dependent P300 regulation of ADAMDEC1

“…We also found NFκB-dependent recruitment of p300 to the enhancers extending our understanding of the mechanisms regulating p300 recruitment (Ong and Corces, 2011). CBP and p300 have been examined as scaffolding proteins supporting NFκB-regulated promoters (Kamitani et al, 2011; Li et al, 2018; Mukherjee et al, 2013). Thus, interactions between NFκB and p300 are well described at promoters.…”

The Signaling of Cellular Senescence in Diabetic Nephropathy

“…In diabetic status, high glucose, AGEs, and oxidative stress could simultaneously induce the activation of NF- κ B, a known transcriptional signature of inflammation [18]. Through recruiting p300, NF- κ B triggers the activation of downstream effector iNOS, a promoter of oxidative stress and inflammation that causes extensive nitrotyrosine (NT) in proteins [159]. Genetic and pharmacological inhibition of NF- κ B signaling prevent age-associated diseases [160–162] including diabetic nephropathy [159] and natural aging [163, 164].…”

Endothelial cells secreted endothelin-1 augments diabetic nephropathy via inducing extracellular matrix accumulation of mesangial cells in ETBR-/- mice

“…Advanced glycation end products increased NF-kappaB-binding activity to the promoter of ET-1 thus to increase ET-1 expression [28]. Researchers reported that C-peptide protected DN by preventing NF-kappaB from recruiting p300 and binding to the inos promoter [29]. Kolati et al demonstrated that NF-kappaB inhibitor BAY 11-7082 ameliorated DN by inhibiting renal inflammation and oxidative stress [30].…”