C-peptide as a Therapy for Kidney Disease: A Systematic Review and Meta-Analysis

Shaw, James; Shetty, Partha; Burns, Kevin D.; Fergusson, Dean; Knoll, Greg

doi:10.1371/journal.pone.0127439

Cited by 20 publications

(15 citation statements)

References 43 publications

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“…CP has emerged as an effective treatment for DN (8)(9)(10)(11)(12)(13)32). Several mechanisms have been reported for the protective effects of CP (14).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

FASEB j.

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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.

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“…CP has emerged as an effective treatment for DN (8)(9)(10)(11)(12)(13)32). Several mechanisms have been reported for the protective effects of CP (14).…”

Section: Discussionmentioning

confidence: 99%

“…C-peptide (CP) has unique reversal effects on DN (8)(9)(10)(11). For example, the physiologic concentration of CP can reverse glomerular fibrosis and recover renal function in DM (12,13).…”

mentioning

confidence: 99%

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

et al. 2018

FASEB j.

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“…In vivo studies in animal models of T1DM showed positive effects of C‐peptide on early stages of nephropathy, retinopathy, and neuropathy . In addition, clinical trials in humans with T1DM and T2DM suggested beneficial impact of C‐peptide on kidney, retina, and nerve . High doses of C‐peptide were capable to reduce thrombus formation .…”

Section: Introductionmentioning

confidence: 98%

“…peptide on kidney, 10 retina, 11 and nerve. [12][13][14] High doses of C-peptide were capable to reduce thrombus formation.…”

mentioning

confidence: 96%

The dual effect of C‐peptide on cellular activation and atherosclerosis: Protective or not?

Alves

Ortiz

Reis

et al. 2018

Diabetes Metabolism Res

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C-peptide is a cleavage product of proinsulin that acts on different type of cells, such as blood and endothelial cells. C-peptide biological effects may be different in type 1 and type 2 diabetes. Besides, there are further evidence for a functional interaction between C-peptide and insulin. In this way, C-peptide has ambiguous effects, acting as an antithrombotic or thrombotic molecule, depending on the physiological environment and disease conditions. Moreover, C-peptide regulates interaction of leucocytes, erythrocytes, and platelets with the endothelium. The beneficial effects include stimulation of nitric oxide production with its subsequent release by platelets and endothelium, the interaction with erythrocytes leading to the generation of adenosine triphosphate, and inhibition of atherogenic cytokine release. The undesirable action of C-peptide includes the chemotaxis of monocytes, lymphocytes, and smooth muscle cells. Also, C-peptide was related with increased lipid deposits and elevated smooth muscle cells proliferation in the vessel wall, contributing to atherosclerosis. Purpose of this review is to explore these dual roles of C-peptide on the blood, contributing at one side to haemostasis and the other to atherosclerotic process.

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“…Although excess TGFB1/SMAD3stimulated COL4 synthesis has been established to be a major contributor to ECM accumulation in DN, there is still no effective therapy. C-peptide links the A and B chains of proinsulin, but has been found to have unique beneficial effects on DN (Shaw et al 2015, Wahren & Larsson 2015. In animal models or in humans with type 1 diabetes, C-peptide can reduce glomerular hyperfiltration and albuminuria (Brunskill 2017).…”

Section: Introductionmentioning

confidence: 99%

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

Zhong

Gong

et al. 2018

Journal of Molecular Endocrinology

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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.

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C-peptide as a Therapy for Kidney Disease: A Systematic Review and Meta-Analysis

Cited by 20 publications

References 43 publications

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

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

The dual effect of C‐peptide on cellular activation and atherosclerosis: Protective or not?

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

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