HMGB1, TGF‑β and NF‑κB are associated with chronic allograft nephropathy

Zhao, Shuai; Xue, Zhenzhen; Wang, Ling-Zhang

doi:10.3892/etm.2017.5319

Cited by 4 publications

(3 citation statements)

References 53 publications

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“…23,39 Previous studies reported that the activation of NF-κB is closely associated with the development and progression of CRAD. 40,41 Moreover, deficiency of NF-κB significantly attenuates the inflammatory response, alleviates tissue damage, and improves the survival of renal allografts. 42 The high expression of RANTES and MCP-1 is closely related to inflammatory cell infiltration and IF/TA in patients with CRAD.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats

et al. 2020

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Background. Chronic renal allograft dysfunction (CRAD) is a major condition that impedes the long-term survival of renal allografts. However, the mechanism of CRAD is obscure, and the effective strategies for controlling the progression of CRAD are lacking. The present study used a CRAD rat model to assess the effect of glycogen synthase kinase 3β (GSK-3β) inhibition on the development of CRAD. Methods. A classical F334-to-LEW orthotopic renal transplantation was performed on the CRAD group. The treatment group was treated with the GSK-3β inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione for 12 consecutive weeks following renal transplantation. The study included uninephrectomized F344 and Lewis rats as control subjects. Twelve weeks post surgery, the rats were retrieved for analysis of renal function, urine protein levels, histological, immunohistochemical, and molecular biological parameters. Results. Administration of 4-benzyl-2-methyl-1,2,4thiadiazolidine-3,5-dione inactivated GSK-3β and thereby improved renal function, attenuated proteinuria, and reduced renal tissue damage in CRAD rats. Besides, inactivation of GSK-3β inhibited nuclear factor-κB activation, macrophage infiltration, and expression of multiple proinflammatory cytokines/chemokines. Inhibition of GSK-3β also decreased the levels of malondialdehyde, increased superoxide dismutase levels, upregulated the expression of heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1, and enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 in the kidneys of CRAD rats. Conclusions. Inhibition of GSK-3β attenuates the development of CRAD by inhibiting inflammation and oxidant stress. Thus, GSK-3β inhibition may represent a potential therapeutic strategy for the prevention and treatment of CRAD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats

et al. 2020

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“…Using ELISA at different time points in our iFA model, we also observed increasing levels of secreted HMGB1 during progression of the phenotype (Figure 2F). The secretion and cytoplasmic translocation of nuclear HMGB1 can account for the secretion of pro-inflammatory cytokines and activation of nuclear factor κB (NF-κB) (Kim et al, 2017; Li et al, 2016; López-Novoa and Nieto, 2009; Tadie et al, 2012; Wang et al, 2017; Zhao et al, 2017) (Figure 2G) The activation of NF-κB in our iFA model is seen by its nuclear localization in the cells in our model (Figure 2G). As a damage-associated molecular pattern (DAMP) protein, HMGB1 has been reported to be a pro-fibrotic agent in liver, renal, and lung fibrosis (Hamada et al, 2008; Li et al, 2014).…”

Section: Resultsmentioning

confidence: 83%

Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule

et al. 2019

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SUMMARY Progressive organ fibrosis accounts for one-third of all deaths worldwide, yet preclinical models that mimic the complex, progressive nature of the disease are lacking, and hence, there are no curative therapies. Progressive fibrosis across organs shares common cellular and molecular pathways involving chronic injury, inflammation, and aberrant repair resulting in deposition of extracellular matrix, organ remodeling, and ultimately organ failure. We describe the generation and characterization of an in vitro progressive fibrosis model that uses cell types derived from induced pluripotent stem cells. Our model produces endogenous activated transforming growth factor β (TGF-β) and contains activated fibroblastic aggregates that progressively increase in size and stiffness with activation of known fibrotic molecular and cellular changes. We used this model as a phenotypic drug discovery platform for modulators of fibrosis. We validated this platform by identifying a compound that promotes resolution of fibrosis in in vivo and ex vivo models of ocular and lung fibrosis.

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“…In heart transplantation recipient patients, the expression of TGF-β in cardiac biopsy specimens was strongly associated with the development of vasculopathy ( 20 ). A positive association between HMGB1 and TGF-β1 expression was identified in chronic allograft nephropathy ( 11 ). TGF-β has 3 isoforms including TGF-β1, -β2, and -β3.…”

Section: Discussionmentioning

confidence: 99%

Extracellular HMGB1 Contributes to the Chronic Cardiac Allograft Vasculopathy/Fibrosis by Modulating TGF-β1 Signaling

Zou

Ming

et al. 2021

Front. Immunol.

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Cardiac allograft vasculopathy (CAV) charactered with aberrant remodeling and fibrosis usually leads to the loss of graft after heart transplantation. Our previous work has reported that extracellular high-mobility group box 1 (HMGB1) participated in the CAV progression via promoting inflammatory cells infiltration and immune damage. The aim of this study was to investigate the involvement of HMGB1 in the pathogenesis of CAV/fibrosis and potential mechanisms using a chronic cardiac rejection model in mice. We found high levels of transforming growth factor (TGF)-β1 in cardiac allografts after transplantation. Treatment with HMGB1 neutralizing antibody markedly prolonged the allograft survival accompanied by attenuated fibrosis of cardiac allograft, decreased fibroblasts-to-myofibroblasts conversion, and reduced synthesis and release of TGF-β1. In addition, recombinant HMGB1 stimulation promoted release of active TGF-β1 from cardiac fibroblasts and macrophages in vitro, and subsequent phosphorylation of Smad2 and Smad3 which were downstream of TGF-β1 signaling. These data indicate that HMGB1 contributes to the CAV/fibrosis via promoting the activation of TGF-β1/Smad signaling. Targeting HMGB1 might become a new therapeutic strategy for inhibiting cardiac allograft fibrosis and dysfunction.

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HMGB1, TGF‑β and NF‑κB are associated with chronic allograft nephropathy

Cited by 4 publications

References 53 publications

Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats

Inhibition of Glycogen Synthase Kinase 3β Alleviates Chronic Renal Allograft Dysfunction in Rats

Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule

Extracellular HMGB1 Contributes to the Chronic Cardiac Allograft Vasculopathy/Fibrosis by Modulating TGF-β1 Signaling

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