Thrombospondin-1: A Key Protein That Induces Fibrosis in Diabetic Complications

Xu, Linhao; Zhang, Yong; Chen, Jian; Xu, Yizhou

doi:10.1155/2020/8043135

Cited by 21 publications

(13 citation statements)

References 140 publications

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“…Being involved in atherosclerosis, inflammation, ischemia/reperfusion injury, cardiac hypertrophy, and heart failure, THBS1 plays a significant role in the development of cardiovascular diseases [ 72 ]. In diabetic complications, this molecule is considered to be a key inductor of fibrosis [ 73 ].…”

Section: Resultsmentioning

confidence: 99%

Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications

Saik

Климонтов

2020

IJMS

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Glucose variability (GV) has been recognized recently as a promoter of complications and therapeutic targets in diabetes. The aim of this study was to reconstruct and analyze gene networks related to GV in diabetes and its complications. For network analysis, we used the ANDSystem that provides automatic network reconstruction and analysis based on text mining. The network of GV consisted of 37 genes/proteins associated with both hyperglycemia and hypoglycemia. Cardiovascular system, pancreas, adipose and muscle tissues, gastrointestinal tract, and kidney were recognized as the loci with the highest expression of GV-related genes. According to Gene Ontology enrichment analysis, these genes are associated with insulin secretion, glucose metabolism, glycogen biosynthesis, gluconeogenesis, MAPK and JAK-STAT cascades, protein kinase B signaling, cell proliferation, nitric oxide biosynthesis, etc. GV-related genes were found to occupy central positions in the networks of diabetes complications (cardiovascular disease, diabetic nephropathy, retinopathy, and neuropathy) and were associated with response to hypoxia. Gene prioritization analysis identified new gene candidates (THBS1, FN1, HSP90AA1, EGFR, MAPK1, STAT3, TP53, EGF, GSK3B, and PTEN) potentially involved in GV. The results expand the understanding of the molecular mechanisms of the GV phenomenon in diabetes and provide molecular markers and therapeutic targets for future research.

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Section: Resultsmentioning

confidence: 99%

Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications

Saik

Климонтов

2020

IJMS

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“…TGF-β Pathway Thrombospondin 1 Thrombospondin 1 (THBS1) encodes a common glycoprotein that was originally discovered as a thrombinsensitive protein [25]. It participates in many diseases such as antiphospholipid syndrome and diabetes [26,27]. According to the previous reports, THBS1 expression in the serum increased in patients with CSU and was associated with mast cell degranulation [28].…”

Section: Biomarkers and Their Findings In Urticariamentioning

confidence: 99%

Advanced Biomarkers: Therapeutic and Diagnostic Targets in Urticaria

Zhang

et al. 2021

Int Arch Allergy Immunol

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Urticaria is a type of skin disease characterized by rapid onset of hives (superficial dermis edema, erythema, pruritus, or burning sensation). According to whether the natural course exceeds 6 weeks, urticaria can be divided into acute and chronic urticaria (CU). At present, the evaluation of CU activity mainly depends on the Urticaria Activity Score (UAS), but the evaluation indicators are relatively single, and we need more reliable experimental data for evaluation. We typically summarize advanced biomarkers and several related pathogenic pathways discovered in recent years on urticaria, including the cell adhesion/chemotaxis pathway, interleukin (IL)-6/Janus tyrosine kinase/STAT pathway, IL-17/IL-23 pathway, basophil- and mast cell-related pathway, coagulation/fibrinolysis-related pathways, single-nucleotide polymorphism, and some other pathways. This review aims to find appropriate biomarkers so that we can evaluate disease activity, discover novel therapeutic targets, and predict the patients’ response more accurately to therapeutic agents.

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“…Increased deposition of TSP1 into the ECM under HG conditions has previously been shown (Yevdokimova et al, 2001;Xu et al, 2020). Here we investigated whether its deposition is mediated by csGRP78.…”

Section: Deposition Of Tsp1 In the Ecm Is Mediated By Csgrp78mentioning

confidence: 89%

Cell surface GRP78 regulates TGFβ1-mediated profibrotic responses via TSP1 in diabetic kidney disease

Trink

Lin²,

O’Neil³

et al. 2023

Front. Pharmacol.

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Introduction: Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America, characterized by glomerular accumulation of extracellular matrix (ECM) proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses plays a central role in its pathogenesis. We previously showed that the endoplasmic reticulum resident GRP78 translocates to the cell surface in response to HG, where it mediates Akt activation and downstream profibrotic responses in MC. Transforming growth factor β1 (TGFβ1) is recognized as a central mediator of HG-induced profibrotic responses, but whether its activation is regulated by cell surface GRP78 (csGRP78) is unknown. TGFβ1 is stored in the ECM in a latent form, requiring release for biological activity. The matrix glycoprotein thrombospondin 1 (TSP1), known to be increased in DKD and by HG in MC, is an important factor in TGFβ1 activation. Here we determined whether csGRP78 regulates TSP1 expression and thereby TGFβ1 activation by HG.Methods: Primary mouse MC were used. TSP1 and TGFβ1 were assessed using standard molecular biology techniques. Inhibitors of csGRP78 were: 1) vaspin, 2) the C-terminal targeting antibody C38, 3) siRNA downregulation of its transport co-chaperone MTJ-1 to prevent GRP78 translocation to the cell surface, and 4) prevention of csGRP78 activation by its ligand, active α2-macroglobulin (α2M*), with the neutralizing antibody Fα2M or an inhibitory peptide.Results: TSP1 transcript and promoter activity were increased by HG, as were cellular and ECM TSP1, and these required PI3K/Akt activity. Inhibition of csGRP78 prevented HG-induced TSP1 upregulation and deposition into the ECM. The HG-induced increase in active TGFβ1 in the medium was also inhibited, which was associated with reduced intracellular Smad3 activation and signaling. Overexpression of csGRP78 increased TSP-1, and this was further augmented in HG.Discussion: These data support an important role for csGRP78 in regulating HG-induced TSP1 transcriptional induction via PI3K/Akt signaling. Functionally, this enables TGFβ1 activation in response to HG, with consequent increase in ECM proteins. Means of inhibiting csGRP78 signaling represent a novel approach to preventing fibrosis in DKD.

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Thrombospondin-1: A Key Protein That Induces Fibrosis in Diabetic Complications

Cited by 21 publications

References 140 publications

Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications

Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications

Advanced Biomarkers: Therapeutic and Diagnostic Targets in Urticaria

Cell surface GRP78 regulates TGFβ1-mediated profibrotic responses via TSP1 in diabetic kidney disease

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