C-peptide prevents SMAD3 binding to alpha promoters to inhibit collagen type IV synthesis

Abstract

Activation of transforming growth factor β1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear. In this study, pathological changes, expression of COL4 a1-a5 chains (), COL4 distribution and protein and TGFB1 and SMAD3 protein were first assessed in a rat model of diabetes. Then, rat mesangial cells were treated with high glucose (HG) and/or C-peptide to investigate the underlying mechanism. expression, COL4 protein and secretion, TGFB1 protein, SMAD3 nuclear translocation and binding of SMAD3 to its cognate sites in the promoters of, and were measured. It was found that C-peptide attenuated glomerular pathological changes and suppressed renal mRNA expression, COL4 protein content and TGFB1 protein content. C-peptide had a dose-dependent effect to inhibit mRNA expression, COL4 protein content and secretion, in HG-stimulated mesangial cells. In addition, the HG-induced increase in TGFB1 protein content was significantly reduced by C-peptide. Although not apparently affecting SMAD3 nuclear translocation, C-peptide prevented SMAD3 from binding to its sites in the , and promoters in HG-stimulated mesangial cells. In conclusion, C-peptide could prevent SMAD3 from binding to its sites in the, and promoters, to inhibit COL4 generation. These results may provide a mechanism for the alleviation of fibrosis in DN by C-peptide.

Proteome Characterization of BALF Extracellular Vesicles in Idiopathic Pulmonary Fibrosis: Unveiling Undercover Molecular Pathways

“…Its signaling involves ERK1/2, PI3K-Akt, PKC, eNOS and NF-kB, well-known factors in TGF-β signaling [43,44], the key regulator of fibrosis, thereby suggesting C-peptide involvement in fibrogenic processes [45]. Indeed, recent studies show an association of C-peptide with fibrosis progression in different pathologies [46,47]. Some studies have reported the association of C-peptide with the transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) [48], whose modulation balances adipogenesis and fibrogenesis [49], in line with the concept of metabolic dysregulation as an additional impacting cause of fibrosis, especially in IPF [45,49].…”

C‐peptide, glycaemic control, and diabetic complications in type 2 diabetes mellitus: A real‐world study

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Complexities of the glomerular basement membrane

“…Diminished expression and activity of matrix-degrading enzymes and their natural inhibitors might also contribute to the accumulation of matrix in DKD 155,[158][159][160] .…”