C-peptide ameliorates renal injury in type 2 diabetic rats through protein kinase A-mediated inhibition of fibronectin synthesis

Xu, Shiqing; Jiang, Yongwei; Wang, Hui; Wang, Zai; Liu, Honglin; Peng, Liang; Fang, Qing; Deng, Tingting; You, Jungmok; Zhou, Xiaofeng; Zhang, Wenjian; Lou, Jinning

doi:10.1016/j.bbrc.2015.02.022

Cited by 15 publications

(20 citation statements)

References 33 publications

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“…Our previous study found that bonding of AGEs-RAGE contributed to DN by an up-regulation of PKC-β and a down-regulation of PKA, thereby promoting DN via oxidative stress [4]. Moreover, the glomerular accumulation of FN was also correlated with an up-regulation of RAGE and a down-regulation of PKA [25]. In this study, progenitor cell-derived islets could reduce DN by lowering RAGE and PKC but increasing PKA in glomeruli.…”

Section: Discussionmentioning

confidence: 99%

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Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy

Jiang

Zhang

et al. 2017

J Transl Med

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BackgroundDiabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem.ObjectiveTo evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM.MethodsPancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCβ), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD).ResultsIslet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCβ became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined.ConclusionsDN may be reversed by transplantation of human fetal pancreatic progenitor cell-derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1253-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…And C-peptide was efficacious for diabetic microangiopathy, especially DN [27–30]. Dosing of C-peptide could significantly improve renal size, morphology and function in DN rats [25, 31–33]. In humans, short and long-term treatments of C-peptide affected renal regulatory and physiological functions in type I DM [34–36].…”

Section: Discussionmentioning

confidence: 99%

Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy

Jiang

Zhang

et al. 2017

J Transl Med

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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). Several mechanisms have been reported for the protective effects of CP (14)(15)(16)(17); however, these pathways are not specific to DN and do not describe the unique beneficial effects of CP.…”

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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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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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“…The PKC-β isoforms are major players in the pathological changes involved in the renal injury that accompanies DM [25]. Moreover, activation of RAGE leads to up-regulation of PKC-β and down-regulation PKA, thereby promoting renal injury [26,27] (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Adiponectin Against Diabetic Renal Injury in a Mouse Model of Diabetes

Hu¹,

Dong²,

Yang³

et al. 2017

Cell Physiol Biochem

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Abstract:Background/Aims: Adiponectin (Apn) has shown anti-diabetic and anti-inflammatory potential. In the study, we studied and tested the protective effects of Apn against diabetic renal injury and the possible mechanism of these effects. Methods: After 1 week of adaptive feeding, 30 mice were randomly divided into 5 groups: the control group, the model group, the Apn (L) group, the Apn (M) group and the Apn (H) group. All mice were marked and weighed. Following 4 weeks of a pro-diabetic high-fat diet, the model group and Apn groups were injected intraperitoneally with a high dose of STZ (85 mg/kg), while the normal control group was injected with sodium citrate. Fasting blood glucose was measured daily, starting 3 days after STZ injection. After confirming the success of the diabetic model by measuring blood glucose of more than 16.7 nM for 3 successive days, we observed the animal models for an additional 4 weeks. After body weights were measured, urinary albumin, urinary protein, SOD activity and malondialdehyde (MDA) were measured by ELISA, BCA and biochemical assay respectively . Moreover, plasma insulin was assayed by radioimmunoassay, insulin expression in pancreatic β cells was assayed by immunohistochemistry and receptor for advanced glycation end products (RAGE) and corresponding PKC and PKA signaling in the kidney cortex were also assayed by Western blot and Real-time PCR. Results: The results showed that Apn can significantly reduce MDA and enhance SOD activity. Moreover, Apn promoted the synthesis and secretion of insulin by islet β-cells and reduced RAGE accumulation in the kidney, which was associated with down-regulated PKC expression and upregulated PKA expression. Conclusion: Apn has protective effects against hyperglycemia and can effectively enhance antioxidation, promote the secretion of insulin and reduce the accumulation of glycosylated products in T2DM mice; these effects were associated with inhibition of PKC and promotion of PKA signaling.

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C-peptide ameliorates renal injury in type 2 diabetic rats through protein kinase A-mediated inhibition of fibronectin synthesis

Cited by 15 publications

References 33 publications

Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy

Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy

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

Protective Effects of Adiponectin Against Diabetic Renal Injury in a Mouse Model of Diabetes

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