The effect of C-peptide on diabetic nephropathy: A review of molecular mechanisms

Objectives. Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) throughout the world, and the identification of novel biomarkers via bioinformatics analysis could provide research foundation for future experimental verification and large-group cohort in DN models and patients. Methods. GSE30528, GSE47183, and GSE104948 were downloaded from Gene Expression Omnibus (GEO) database to find differentially expressed genes (DEGs). The difference of gene expression between normal renal tissues and DN renal tissues was firstly screened by GEO2R. Then, the protein-protein interactions (PPIs) of DEGs were performed by STRING database, the result was integrated and visualized via applying Cytoscape software, and the hub genes in this PPI network were selected by MCODE and topological analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to determine the molecular mechanisms of DEGs involved in the progression of DN. Finally, the Nephroseq v5 online platform was used to explore the correlation between hub genes and clinical features of DN. Results. There were 64 DEGs, and 32 hub genes were identified, enriched pathways of hub genes involved in several functions and expression pathways, such as complement binding, extracellular matrix structural constituent, complement cascade related pathways, and ECM proteoglycans. The correlation analysis and subgroup analysis of 7 complement cascade-related hub genes and the clinical characteristics of DN showed that C1QA, C1QB, C3, CFB, ITGB2, VSIG4, and CLU may participate in the development of DN. Conclusions. We confirmed that the complement cascade-related hub genes may be the novel biomarkers for DN early diagnosis and targeted treatment.

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Long Non-Coding RNA NEAT1 Regulates Pyroptosis in Diabetic Nephropathy via Mediating the miR-34c/NLRP3 Axis

Kidney & Blood Pressure Research ◽

10.1159/000508372 ◽

2020 ◽

Vol 45 (4) ◽

pp. 589-602 ◽

Cited By ~ 1

Author(s):

Jin-Feng Zhan ◽

Hong-Wei Huang ◽

Chong Huang ◽

Li-Li Hu ◽

Wen-Wei Xu

Keyword(s):

Diabetic Nephropathy ◽

Target Gene ◽

Molecular Mechanisms ◽

Mesangial Cells ◽

Receptor Protein ◽

Luciferase Reporter ◽

Glomerular Mesangial Cells ◽

Non Coding Rna ◽

Vitro Model

Introduction: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and is considered to be a sterile inflammatory disease. Increasing evidence suggest that pyroptosis and subsequent inflammatory response play a key role in the pathogenesis of DN. However, the underlying cellular and molecular mechanisms responsible for pyroptosis in DN are largely unknown. Methods: The rat models of DN were successfully established by single 65 mg/kg streptozotocin treatment. Glomerular mesangial cells were exposed to 30 mmol/L high glucose media for 48 h to mimic the DN environment in vitro. Gene and protein expressions were determined by quantitative real-time PCR and Western blot. Cell viability and pyroptosis were measured by MTT assay and flow cytometry analysis, respectively. The relationship between lncRNA NEAT1, miR-34c, and Nod-like receptor protein-3 (NLRP3) was confirmed by luciferase reporter assay. Results: We found that upregulation of NEAT1 was associated with the increase of pyroptosis in DN models. miR-34c, as a target gene of NEAT1, mediated the effect of NEAT1 on pyroptosis in DN by regulating the expression of NLRP3 as well as the expressions of caspase-1 and interleukin-1β. Either miR-34c inhibition or NLRP3 overexpression could reverse the accentuation of pyroptosis and inflammation by sh-NEAT1 transfection in the in vitro model of DN. Conclusions: Our findings suggested NEAT1 and its target gene miR-34c regulated cell pyroptosis via mediating NLRP3 in DN, providing new insights into understanding the molecular mechanisms of pyroptosis in the pathogenesis of DN.

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A Network Pharmacology Approach to Uncover the Mechanisms of Shen-Qi-Di-Huang Decoction against Diabetic Nephropathy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/7043402 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 9

Author(s):

Sha Di ◽

Lin Han ◽

Qing Wang ◽

Xinkui Liu ◽

Yingying Yang ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Interaction Network ◽

Enrichment Analysis ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Protein Protein Interaction ◽

Regulation Of Blood Pressure ◽

Protein Protein Interaction Network

Shen-Qi-Di-Huang decoction (SQDHD), a well-known herbal formula from China, has been widely used in the treatment of diabetic nephropathy (DN). However, the pharmacological mechanisms of SQDHD have not been entirely elucidated. At first, we conducted a comprehensive literature search to identify the active constituents of SQDHD, determined their corresponding targets, and obtained known DN targets from several databases. A protein-protein interaction network was then built to explore the complex relations between SQDHD targets and those known to treat DN. Following the topological feature screening of each node in the network, 400 major targets of SQDHD were obtained. The pathway enrichment analysis results acquired from DAVID showed that the significant bioprocesses and pathways include oxidative stress, response to glucose, regulation of blood pressure, regulation of cell proliferation, cytokine-mediated signaling pathway, and the apoptotic signaling pathway. More interestingly, five key targets of SQDHD, named AKT1, AR, CTNNB1, EGFR, and ESR1, were significant in the regulation of the above bioprocesses and pathways. This study partially verified and predicted the pharmacological and molecular mechanisms of SQDHD on DN from a holistic perspective. This has laid the foundation for further experimental research and has expanded the rational application of SQDHD in clinical practice.

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Immunoinflammation in Diabetic Nephropathy: Molecular Mechanisms and Therapeutic Options

Diabetic Nephropathy ◽

10.5772/34541 ◽

2012 ◽

Cited By ~ 8

Author(s):

Virginia Lopez-Parra ◽

Beat Mallavia ◽

Jesus Egido ◽

Carmen Gomez-Guerrero

Keyword(s):

Diabetic Nephropathy ◽

Molecular Mechanisms ◽

Therapeutic Options

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Expression Profiling and Clinical Significance of Plasma MicroRNAs in Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2019/5204394 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Jianqin Wang ◽

Gouqin Wang ◽

Yaojun Liang ◽

Xiaochun Zhou

Keyword(s):

Diabetic Nephropathy ◽

Clinical Significance ◽

Expression Profiling ◽

Molecular Mechanisms ◽

Clinicopathological Parameters ◽

Diabetic Patients ◽

Healthy Controls ◽

Plasma Samples ◽

Expression Levels ◽

Plasma Mirnas

Aims. MicroRNAs (miRNAs) stably and abundantly exist in body fluids and have been considered as novel and noninvasive biomarkers for several diseases. The present study is aimed at investigating the expression profiling and clinical significance of plasma miRNAs in the pathogenesis and progression of diabetic nephropathy (DN). Methods. Plasma samples were obtained from 66 DN patients (36 had microalbuminuria and 30 had macroalbuminuria), 36 diabetic patients with normoalbuminuria, and 40 healthy controls. The plasma miRNA profiles were obtained by miRNA low-density array chip and validated by quantitative real-time polymerase chain reaction. The correlations between the differential expression of plasma miRNAs and clinicopathological parameters were explored. Results. miR-150-5p, miR-155-5p, miR-30e, miR-320e, and miR-3196 were found to be differentially expressed in plasma samples among these three groups: diabetic patients with microalbuminuria, diabetic patients with normoalbuminuria, and healthy controls (P<0.05). The expression levels of miR-150-5p and miR-155-5p in patients with macroalbuminuria were 2.3-fold (P=0.001) and 1.5-fold (P=0.033) higher than patients with microalbuminuria, respectively. However, the expression levels of miR-30e, miR-3196, miR-320, and let-7a-5p were not significantly different between these two groups (P>0.05). Furthermore, plasma miR-150-5p (P=0.016, r = -0.460) and miR-155-5p (P=0.014, r = -0.467) were negatively correlated with the albuminuria excretion rate, while plasma miR-150-5p (P=0.01, r = 0.318) and miR-155-5p (P=0.030, r=0.271) were positively correlated with the estimated glomerular filtration rate. Conclusion. miR-150-5p, miR-155-5p, miR-30e, miR-320e, and miR-3196 are potentially new diagnostic biomarkers for early DN. miR-150-5p and miR-155-5p may be involved in the pathogenesis and progression of DN. Further research is required to verify these findings and clarify the specific molecular mechanisms.

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Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms

Trends in Endocrinology and Metabolism ◽

10.1016/j.tem.2016.07.002 ◽

2016 ◽

Vol 27 (11) ◽

pp. 820-830 ◽

Cited By ~ 119

Author(s):

Luigi Gnudi ◽

Richard J.M. Coward ◽

David A. Long

Keyword(s):

Diabetic Nephropathy ◽

Molecular Mechanisms

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Molecular mechanisms of action and physiological effects of the proinsulin C-peptide (a systematic review)

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20206603196 ◽

2020 ◽

Vol 66 (3) ◽

pp. 196-207

Author(s):

O.N. Poteryaeva ◽

I.F. Usynin

Keyword(s):

Intracellular Signaling ◽

Defense Mechanisms ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Experimental Models ◽

Physiological Effects ◽

C Peptide ◽

Downstream Signaling ◽

Blood Microcirculation ◽

Patients With Diabetes

The C-peptide is a fragment of proinsulin, the cleavage of which forms active insulin. In recent years, new information has appeared on the physiological effects of the C-peptide, indicating its positive effect on many organs and tissues, including the kidneys, nervous system, heart, vascular endothelium and blood microcirculation. Studies on experimental models of diabetes mellitus in animals, as well as clinical trials in patients with diabetes, have shown that the C-peptide has an important regulatory effect on the early stages of functional and structural disorders caused by this disease. The C-peptide exhibits its effects through binding to a specific receptor on the cell membrane and activation of downstream signaling pathways. Intracellular signaling involves G-proteins and Ca2+-dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+/K+-ATPase and important transcription factors involved in apoptosis, anti-inflammatory and other intracellular defense mechanisms. This review gives an idea of the C-peptide as a bioactive endogenous peptide that has its own biological activity and therapeutic potential.

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Prediction of the molecular mechanisms and potential therapeutic targets for diabetic nephropathy by bioinformatics methods

International Journal of Molecular Medicine ◽

10.3892/ijmm.2016.2527 ◽

2016 ◽

Vol 37 (5) ◽

pp. 1181-1188 ◽

Cited By ~ 6

Author(s):

WAN-NING WANG ◽

WEN-LONG ZHANG ◽

GUANG-YU ZHOU ◽

FU-ZHE MA ◽

TAO SUN ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Molecular Mechanisms ◽

Therapeutic Targets

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Proteasome Activators, PA28α and PA28β, Govern Development of Microvascular Injury in Diabetic Nephropathy and Retinopathy

International Journal of Nephrology ◽

10.1155/2016/3846573 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Saeed Yadranji Aghdam ◽

Ali Mahmoudpour

Keyword(s):

Diabetic Nephropathy ◽

High Glucose ◽

Molecular Mechanisms ◽

Mesangial Cells ◽

Diabetic Mice ◽

Double Knockout ◽

Monocyte Chemoattractant Protein 1 ◽

Microvascular Injury ◽

Retinal Pericytes ◽

Diabetes Model

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are major complications of type 1 and type 2 diabetes. DN and DR are mainly caused by injury to the perivascular supporting cells, the mesangial cells within the glomerulus, and the pericytes in the retina. The genes and molecular mechanisms predisposing retinal and glomerular pericytes to diabetic injury are poorly characterized. In this study, the genetic deletion of proteasome activator genes, PA28α and PA28β genes, protected the diabetic mice in the experimental STZ-induced diabetes model against renal injury and retinal microvascular injury and prolonged their survival compared with wild type STZ diabetic mice. The improved wellbeing and reduced renal damage was associated with diminished expression of Osteopontin (OPN) and Monocyte Chemoattractant Protein-1 (MCP-1) in the glomeruli of STZ-injected PA28α/PA28β double knockout (Pa28αβDKO) mice and also in cultured mesangial cells and retinal pericytes isolated from Pa28αβDKO mice that were grown in high glucose. The mesangial PA28-mediated expression of OPN under high glucose conditions was suppressed by peptides capable of inhibiting the binding of PA28 to the 20S proteasome. Collectively, our findings demonstrate that diabetic hyperglycemia promotes PA28-mediated alteration of proteasome activity in vulnerable perivascular cells resulting in microvascular injury and development of DN and DR.

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A Network Pharmacology-Based Approach for Exploring Key Active Compounds and Pharmacological Mechanisms of Tangshen Formula for Treatment of Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2021/8833688 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Weie Zhou ◽

Xuefeng Zhou ◽

Yuan Zhang ◽

Yuyang Wang ◽

Wenjie Wu ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Synergistic Effects ◽

Mapk Signaling ◽

Network Pharmacology ◽

Active Compounds ◽

Promising Source ◽

Tangshen Formula ◽

Compound Target

Diabetic nephropathy (DN) is one of the common and severe microvascular complications of diabetes mellitus (DM). The occurrence and development of DN are related to multiple factors in the human body, which makes DN a complex disease, and the pathogeneses of DN have not yet been fully illustrated. Furthermore, DN lacks effective drugs for treatment nowadays. Chinese herbal medicine (CHM) often shows the feature of multicomponents, multitargets, multipathways, and synergistic effects and shows a promising source of new therapeutic drugs for DN. As a CHM, Tangshen Formula (TSF) was used to treat DN patients in China. However, its bioactive compounds and holistic pharmacological mechanisms on DN are both unclear. A network pharmacology approach was firstly applied to explore multiple active compounds and multiple key pharmacological mechanisms for TSF treating DN by drug-targeted interaction databases, herb-compound-target network, protein-protein interaction network, compound-target-pathway network, and analysis methods. And the results showed that TSF have the characteristic of multicomponents, multitargets, multipathways, and synergistic effects for treating DN. The quercetin, naringenin, kaempferol, and isorhamnetin as key active compounds and the PI3K-Akt signaling pathway, TNF signaling pathway, nonalcoholic fatty liver disease (NAFLD), focal adhesion, rap1 signaling pathway, T cell receptor signaling pathway, MAPK signaling pathway, and insulin resistance as the key molecular mechanisms play important roles in TSF treating DN. Moreover, quercetin, naringenin, kaempferol, and isorhamnetin were successfully detected in TSF by the UHPLC-MS/MS analysis method. And their concentrations were 0.224, 8.295, 0.0564, and 0.0879 mg·kg-1, respectively. The present findings not only provide new insights for a deeper understanding of the constituent basis and pharmacology of TSF but also provide guidance for further pharmacological studies on TSF.

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