Spleen tyrosine kinase promotes NLR family pyrin domain containing 3 inflammasome‑mediated IL‑1β secretion via c‑Jun N‑terminal kinase activation and cell apoptosis during diabetic nephropathy

Qiao, Yingchun; Tian, Xixi; Men, Li; Li, Shengyu; Chen, Yufeng; Xue, Meiting; Hu, Yahui; Zhou, Pengfei; Long, Guangfeng; Shi, Yue; Liu, Ruiqing; Liu, Yunde; Qi, Zhi; Cui, Yujie; Shen, Yanna

doi:10.3892/mmr.2018.9164

Cited by 20 publications

(18 citation statements)

References 48 publications

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“…To date, there have been some reports about hub genes and DN. Spleen tyrosine kinase (SYK) was reported to mediate high glucose-induced TGF-β1 and IL-1β secretion 18,19 . In a diabetic animal model, C-X-C motif chemokine ligand 1 (CXCL1) was found to possibly serve as a proinflammatory mediator 20,21 .…”

Section: Discussionmentioning

confidence: 99%

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Tang

Wang

Deng

et al. 2020

Sci Rep

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The pathogenesis of diabetic nephropathy is not completely understood, and the effects of existing treatments are not satisfactory. Various public platforms already contain extensive data for deeper bioinformatics analysis. From the GSE30529 dataset based on diabetic nephropathy tubular samples, we identified 345 genes through differential expression analysis and weighted gene coexpression correlation network analysis. GO annotations mainly included neutrophil activation, regulation of immune effector process, positive regulation of cytokine production and neutrophil-mediated immunity. KEGG pathways mostly included phagosome, complement and coagulation cascades, cell adhesion molecules and the AGE-RAGE signalling pathway in diabetic complications. Additional datasets were analysed to understand the mechanisms of differential gene expression from an epigenetic perspective. Differentially expressed miRNAs were obtained to construct a miRNA-mRNA network from the miRNA profiles in the GSE57674 dataset. The miR-1237-3p/SH2B3, miR-1238-5p/ ZNF652 and miR-766-3p/TGFBI axes may be involved in diabetic nephropathy. The methylation levels of the 345 genes were also tested based on the gene methylation profiles of the GSE121820 dataset. The top 20 hub genes in the PPI network were discerned using the CytoHubba tool. Correlation analysis with GFR showed that SYK, CXCL1, LYN, VWF, ANXA1, C3, HLA-E, RHOA, SERPING1, EGF and KNG1 may be involved in diabetic nephropathy. Eight small molecule compounds were identified as potential therapeutic drugs using Connectivity Map. It is estimated that a total of 451 million people suffered from diabetes by 2017, and the number is speculated to be 693 million by 2045 1. As one of the most serious microvascular complications, diabetic nephropathy (DN) has been a major cause of end-stage renal disease (ESRD) in many countries. The congregation of advanced glycation end-products, oxidative stress and activation of protein kinase C are the major pathogeneses of DN. A new viewpoint holds that tubular injury plays an important and even initial role 2. Current treatment strategies for DN aim at controlling blood glucose and blood pressure levels and inhibiting the RAS system to reduce albuminuria and delay the progression of DN 3. However, considering the high incidence of DN-related ESRD, the effect is not entirely satisfactory. Therefore, there is a critical need to identify new therapeutic targets and improve clinical management. High-throughput sequencing technology offers an effective method to study disease-related genes and provides promising medication goals in many fields 4. To date, several studies have screened genes or miRNAs involved in DN 5-9. Integrating these data could overcome the heterogeneity of studies and provide more accurate information. This study identified target genes that may improve the understanding of the molecular mechanisms of DN and provide a resource to build new hypotheses for further follow-up studies. We suggest that the complement system may serve as a thera...

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Section: Discussionmentioning

confidence: 99%

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Tang

Wang

Deng

et al. 2020

Sci Rep

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“…Qiao et al have established the Syk/JNK/NLRP3 signaling axis might play a crucial role in DN. 139 A recent study documented that decreased GAS5 expression could promote TNF-α, IL-6, MCP-1, ROS expression levels in HG-stimulated renal tubular cells. 140 Besides, reduced GAS5 expression can significantly promote NLRP3, caspase-1, IL-1β, and GSDMD-N expression levels, and the results of immunofluorescence confirmed the critical findings.…”

Section: Diabetic Nephropathy (Dn)mentioning

confidence: 99%

Role of Pyroptosis in Diabetes and Its Therapeutic Implications

Mamun¹,

Wu²,

Nasrin³

et al. 2021

JIR

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Pyroptosis is mainly considered as a new pro-inflammatory mediatedprogrammed cell death. In addition, pyroptosis is described by gasdermin-induced pore formation on the membrane, cell swelling and rapid lysis, and several pro-inflammatory mediators interleukin-1β (IL-1β) and interleukin-18 (IL-18) release. Extensive studies have shown that pyroptosis is commonly involved by activating the caspase-1-dependent canonical pathway and caspase-4/5/11-dependent non-canonical pathway. However, pyroptosis facilitates local inflammation and inflammatory responses. Current researches have reported that pyroptosis promotes the progression of several diabetic complications. Emerging studies have suggested that some potential molecules targeting the pyroptosis and inflammasome signaling pathways could be a novel therapeutic avenue for managing and treating diabetes and its complications in the near future. Our narrative review concisely describes the possible mechanism of pyroptosis and its progressive understanding of the development of diabetic complications.

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“…Administration of Syk-siRNA can inhibit JNK activation under HG concentration. Meanwhile, the NLRP3 inflammasome and IL-1β are significantly down-expressed in HK2 cells and RGMCs [ 96 , 97 ].…”

Section: Pyroptosis Regulatory Pathways In Dkdmentioning

confidence: 99%

New Insights into the Mechanisms of Pyroptosis and Implications for Diabetic Kidney Disease

Lin

Cheng

et al. 2020

IJMS

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Pyroptosis is one special type of lytic programmed cell death, featured in cell swelling, rupture, secretion of cell contents and remarkable proinflammation effect. In the process of pyroptosis, danger signalling and cellular events are detected by inflammasome, activating caspases and cleaving Gasdermin D (GSDMD), along with the secretion of IL-18 and IL-1β. Pyroptosis can be divided into canonical pathway and non-canonical pathway, and NLRP3 inflammasome is the most important initiator. Diabetic kidney disease (DKD) is one of the most serious microvascular complications in diabetes. Current evidence reported the stimulatory role of hyperglycaemia-induced cellular stress in renal cell pyroptosis, and different signalling pathways have been shown to regulate pyroptosis initiation. Additionally, the inflammation and cellular injury caused by pyroptosis are tightly implicated in DKD progression, aggravating renal fibrosis, glomerular sclerosis and tubular injury. Some registered hypoglycaemia agents exert suppressive activity in pyroptosis regulation pathway. Latest studies also reported some potential approaches to target the pyroptosis pathway, which effectively inhibits renal cell pyroptosis and alleviates DKD in in vivo or in vitro models. Therefore, comprehensively compiling the information associated with pyroptosis regulation in DKD is the main aim of this review, and we try to provide new insights for researchers to dig out more potential therapies of DKD.

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Spleen tyrosine kinase promotes NLR family pyrin domain containing 3 inflammasome‑mediated IL‑1β secretion via c‑Jun N‑terminal kinase activation and cell apoptosis during diabetic nephropathy

Cited by 20 publications

References 48 publications

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Role of Pyroptosis in Diabetes and Its Therapeutic Implications

New Insights into the Mechanisms of Pyroptosis and Implications for Diabetic Kidney Disease

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