C-Peptide as a Therapeutic Tool in Diabetic Nephropathy

Hills, Claire E.; Brunskill, Nigel J.; Squires, Paul E.

doi:10.1159/000289864

Cited by 70 publications

(49 citation statements)

References 103 publications

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“…(Fiorina et al 2003(Fiorina et al , 2005. Recent studies have indicated that C-peptide produced by islet cells might help to prevent and treat diabetic microvascular lesions (Cotter et al 2003, Forst & Kunt 2004, Hills et al 2010. In fact, several human trials and animal studies have demonstrated that C-peptide can improve the kidney structural and functional abnormalities of diabetic nephropathy (Hills et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have indicated that C-peptide produced by islet cells might help to prevent and treat diabetic microvascular lesions (Cotter et al 2003, Forst & Kunt 2004, Hills et al 2010. In fact, several human trials and animal studies have demonstrated that C-peptide can improve the kidney structural and functional abnormalities of diabetic nephropathy (Hills et al 2010). Samnegard et al (2005) reported a marked decrease in proteinuria and mesangial matrix synthesis in diabetic nephropathy rats treated with Cpeptide compared with those treated with placebo.…”

Section: Discussionmentioning

confidence: 99%

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Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Ke¹,

Li²,

Xu³

et al. 2013

Journal of Endocrinology

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The efficacy of gliquidone for the treatment of diabetic nephropathy was investigated by implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of Goto-Kakizaki (GK) rats with diabetic nephropathy. Blood glucose, 24 h urinary protein, and 24 h urinary albumin levels were measured weekly. After 4 weeks of gliquidone therapy, pathological changes in the glomerular basement membrane (GBM) were examined using an electron microscope. Real-time PCR, western blotting, and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE) (AGER), protein kinase C b (PKCb), and protein kinase A (PKA) as well as tubular expression of the albumin reabsorption-associated proteins: megalin and cubilin. Human proximal tubular epithelial cells (HK-2 cells) were used to analyze the effects of gliquidone and advanced glycation end products (AGEs) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered blood glucose, 24 h urinary protein, and 24 h urinary albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and GBM and podocyte lesions improved dramatically after gliquidone treatment. Glomerular expression of RAGE and PKCb decreased after gliquidone treatment, while PKA expression increased. AGEs markedly suppressed the expression of megalin and cubulin and the absorption of albumin in HK-2 cells in vitro, whereas the expression of megalin and cubilin and the absorption of albumin were all increased in these cells after gliquidone treatment. In conclusion, gliquidone treatment effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Ke¹,

Li²,

Xu³

et al. 2013

Journal of Endocrinology

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“…A cleavage product of pro-insulin, C-peptide exerts a number of protective affects against the micro-vascular and macro-vascular complications associated with hyperglycaemia in type I diabetes [127] and in those patients with DN, C-peptide is reno-protective [128]. Recently, the Connecting-peptide has been…”

Section: Therapeutic Interventionmentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

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174

187

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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“…Although C-peptide has reversal effects on the fibrosis of glomerular in DN (18)(19)(20)(21)(22), the underlying mechanism is not clarified. Insufficient MMP-2 and MMP-9 is considered to be a contributor of ECM accumulation (11).…”

Section: Discussionmentioning

confidence: 99%

“…Lack of C-peptide along with insulin is the primary feature of type 1 DM and late stage of type 2 DM (16). C-peptide has been found to have unique beneficial effects on DN, attenuating glomerular and tubular injury (17)(18)(19). Physiological concentration of C-peptide can reverse the fibrosis of glomerular and recover renal function in .…”

mentioning

confidence: 99%

C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Insufficient matrix metalloproteinase (MMP)-9 and MMP-2 is considered to be a contributor of extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can reverse fibrosis, thus exerting a beneficial effect on DN. Whether C-peptide induces MMP-9 and MMP-2 to reverse ECM accumulation is not clear. In the present study, in order to determine ECM metabolism, rat mesangial cells were treated with high glucose (HG) and C-peptide intervention, then the early and late effects of C-peptide on HG-affected MMP-9 and MMP-2 were evaluated. Firstly, it was confirmed that HG mainly suppressed MMP-9 expression levels. Furthermore, C-peptide treatment induced MMP-9 expression at 6 h and suppressed it at 24 h, revealing the early dual effects of C-peptide on MMP-9 expression. Subsequently, significant increase in MMP-9 expression at 72, 96 and 120 h C-peptide treatment was observed. These changes in MMP-9 protein content confirmed its expression changes following late C-peptide treatment. Furthermore, at 96 and 120 h C-peptide treatment reversed the HG-inhibited MMP-9 secretion, further indicating the late induction effect of C-peptide on MMP-9. The present results demonstrated that C-peptide exerted a late induction effect on MMP-9 in HG-stimulated rat mesangial cells, which may be associated with the underlying mechanism of C-peptide's reversal effects on DN. IntroductionDiabetic nephropathy (DN), the leading cause of end stage renal disease, is the major cause of mortality in type 1 diabetes mellitus (DM) and the second most severe complications in type 2 diabetes (1,2). Deposition of extracellular matrix (ECM) in mesangial areas is a feature of DN, and mesangial cells have been proposed to be the determinant of ECM accumulation (3,4). However, the mechanism underlying ECM accumulation in DN is not fully clarified.Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can degrade numerous types of ECM components (5,6). Among others, MMP-2 basally expresses while MMP-9 is an inducible enzyme, both of which primarily degrade types-I and -IV collagen and laminin, major components of ECM (7-9). Generally, MMP-2 and MMP-9 are involved in tumor metastasis (6,10). Furthermore, it has been shown that insufficient MMP-2 and MMP-9 may be a contributor of ECM accumulation in DN (11). However, the expression levels of MMP-2 and MMP-9 in DN remain controversial, and even short-and long-term hyperglycemia may exert differential effects (8,(12)(13)(14). As an inducible enzyme, MMP-9 may be more easily affected in patients with DN (15). Therefore, the changes of MMP-2, and particularly MMP-9, for high glucose (HG) stimulation require clarification.C-peptide is the linker between the A-chain and B-chain of insulin. Lack of C-peptide along with insulin is the primary feature of type 1 DM and late stage of type 2 DM (16). C-peptide has been found to have unique beneficial effects on DN, attenuating glomerular and tubular injury (17)(18)(19). Physiological concentration of C-peptide ca...

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C-Peptide as a Therapeutic Tool in Diabetic Nephropathy

Cited by 70 publications

References 103 publications

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells

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