Exclusive expression of transmembrane TNF aggravates acute glomerulonephritis despite reduced leukocyte infiltration and inflammation

Müller, Martin B.; Hoppe, John M.; Bideak, Andrei; Lux, Moritz; Lindenmeyer, Maja T.; Müller, Susanna; Eltrich, Nuru; Ryffel, Bernhard; Vielhauer, Volker

doi:10.1016/j.kint.2018.08.012

Cited by 12 publications

(10 citation statements)

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“… 17 Generally, proinflammatory cytokine TNF-α interacts with its receptors to induce necrosis. 18 On inhibition of caspase activity, the receptors recruit RIPK1 and RIPK3, then promotes their autophosphorylation. This step causes RIPK1 and RIPK3 to form a complex that promotes the phosphorylation of mixed lineage kinase domain-like pseudokinase (MLKL).…”

Section: Discussionmentioning

confidence: 99%

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Metformin improves renal injury of MRL/lpr lupus-prone mice via the AMPK/STAT3 pathway

Chen

et al. 2022

Lupus Sci Med

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ObjectiveLupus nephritis (LN) is a major complication and cause of death among patients with SLE. This research used in vivo and in vitro experiments to explore the therapeutic potential of metformin in kidney injury from LN-induced inflammation.MethodsIn vivo study, 8-week-old MRL/MpJ-Faslpr/J (MRL/lpr) mice were randomly divided into two groups (n=12 each): daily administration of 0.3 mg/mL metformin in drinking water and control (water only). Body weight and urinary samples were measured biweekly. Mice were sacrificed after 8-week treatment to harvest serum, lymph nodes, spleen and kidneys. In vitro study, human kidney-2 (HK-2) cells were pretreated with 1 mM metformin for 1 hour and then stimulated with 20 µg/mL lipopolysaccharides (LPS) or 10 ng/mL tumour necrosis factor-α (TNF-α) for another 48 hours. Protein was collected for subsequent analysis.ResultsWe found that metformin administration improved renal function in MRL/lpr lupus-prone mice, measured by decreased urea nitrogen and urinary proteins. Metformin reduced immunoglobulin G and complement C3 deposition in glomeruli. The treatment also downregulated systemic and renal inflammation, as seen in decreased renal infiltration of F4/80-positive macrophages and reduced splenic and renal MCP-1 (monocyte chemoattractant protein-1) and TNF-α, and renal IL-1β (interleukin 1β) expression. Metformin administration decreased renal expression of necroptosis markers p-RIPK1 (phosphorylated receptor-interacting protein kinase 1) and p-MLKL, along with tubular injury marker KIM-1 (kidney injury molecule-1) in lupus mice. In addition, metformin alleviated the necroptosis of HK-2 cells stimulated by LPS and TNF-α, evidencing by a decrease in the expression of necroptosis markers p-RIPK1, p-RIPK3 and p-MLKL, and the inflammasome-related markers NLRP3 (NLR family pyrin domain containing 3), ASC (apoptosis-associated speck-like protein containing a CARD), caspase-1. Mechanistically, metformin treatment upregulated p-AMPK (phosphorylated AMP-activated protein kinase) and downregulated p-STAT3 (phosphorylated signal transducer and activator of transcription 3) expression in the kidneys. Moreover, AMPKα2 knockdown abolished the protective effects of metformin in vitro.ConclusionsMetformin alleviated kidney injury in LN though suppressing renal necroptosis and inflammation via the AMPK/STAT3 pathway.

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Section: Discussionmentioning

confidence: 99%

“…Necroptosis is a proinflammatory mode of cell death 17. Generally, proinflammatory cytokine TNF-α interacts with its receptors to induce necrosis 18. On inhibition of caspase activity, the receptors recruit RIPK1 and RIPK3, then promotes their autophosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Metformin improves renal injury of MRL/lpr lupus-prone mice via the AMPK/STAT3 pathway

Chen

et al. 2022

Lupus Sci Med

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“…TNF is a cytokine that mediates inflammatory kidney diseases, such as immune complex glomerulonephritis produced by macrophages and renal mesangial and tubular epithelial cells. 32 Müller et al 33 found that TNF is an important factor in causing nephropathic changes, which is characterized by increased renal cell death and loss of glomerular endothelial cells. Meanwhile, TNF-α can induce tubular epithelial cell transformation and aggravate renal interstitial fibrosis in glomerulonephritis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Taohong Siwu Decoction in Treating Chronic Glomerulonephritis Using Network Pharmacology and Molecular Docking

et al. 2022

Natural Product Communications

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Background: Based on network pharmacology and molecular docking technology, the pharmacological mechanism of Taohong Siwu Decoction (THSWD) in the treatment of chronic glomerulonephritis (CGN) was analyzed to provide a theoretical basis for the subsequent development of new drugs and the clinical application of Traditional Chinese Medicine (TCM). Methods: Active ingredients of drugs and disease target genes were obtained from Traditional Chinese Medicine Database and Analysis Platform (TCMSP) database and GeneCards database. The “drug component target” network of THSWD was constructed using Cytoscape version 3.8.2 software. The protein interaction was analyzed using STRING platform, the protein–protein interaction (PPI) network was constructed, and the potential protein function modules in the network were mined. Metascape platform was used to analyze “drug component target” and its biological processes and pathways. The clusterProfiler R package was called to perform kyoto encyclopedia of genes and genomes (KEGG) pathway and gene ontology (GO) function enrichment analysis on CGN-related targets regulated by THSWD. Molecular docking verification was performed by AutoDock Vina software. Results: THSWD has 205 target genes and 45 active components, 104 of which are cross with the CGN inflammatory gene. Its main active ingredients, stigmasterol, kaempferol, and sitosterol, have positive relationships with the inflammatory targets of CGN, tumor necrosis factor (TNF), IL-6, AKT1, and MAPK14. THSWD modulates the biological pathway of CGN and mainly acts on TNF-α signal pathway, interleukin-17 signal pathway, etc., whose main functions are response to lipid sugar, heme binding, G protein-coupled amine receptor activity, etc. The results of molecular docking showed that the main active compounds could bind to the core targets and showed good affinity. Conclusion: The molecular mechanism of THSWD in the treatment of CGN from the perspective of network pharmacology are components such as beta-sitosterol, kaempferol, and quercetin and key action targets such as TNF, IL-6, AKT1 protein kinase, and MAPK14 protein kinase play a synergistic role in autoimmune, infection, and inflammatory response-related pathways.

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“…Tumor necrosis factor-α (TNF-α) is a cytokine mediating inflammatory kidney diseases such as immune complex glomerulonephritis, which is produced by macrophages, and by renal mesangial and tubular epithelial cells. TNF-α is suggested to induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells that possibly exacerbates renal interstitial fibrosis in glomerulonephritis (Muller et al 2019;Khan et al 2005;Adachi et al 2015). Vascular endothelial growth factor (VEGF) regulates angiogenesis through endothelial cell proliferation and plays an important role in the repair of damaged glomerular capillaries.…”

Section: Discussionmentioning

confidence: 99%

Exploring the mechanism of Jianpi Qushi Huayu Formula in the treatment of chronic glomerulonephritis based on network pharmacology

Liu

Gao

Qin

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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This study was to explore the effective components, potential targets, and pathways of Jianpi Qushi Huayu Formula (JQHF) for the treatment of chronic glomerulonephritics (CGN). First, the Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), GeneCards, and OMIM databases were used to collect the major active components of JQHF and potential therapeutic targets of CGN. Then, functional enrichment analysis was performed to clarify the mechanisms of the JQHF on CGN. Subsequently, molecular docking was simulated to assess the binding ability of key targets and major active components. Finally, quantitative real-time PCR and western blot were performed for experimental verification of cells in vitro. A total of 55 active ingredients contained and 220 putative identified targets were screened from JQHF, of which 112 overlapped with the targets of CGN and were considered potential therapeutic targets. Then, we found quercetin and kaempferol are two key ingredients of JQHF, which may act on the top 10 screened targets of PPI, affecting CGN through related signal transduction pathways. Subsequently, molecular docking predicted that quercetin and kaempferol bind firm with the top 10 core targets of PPI. Further experiment verified some results and showed that JQHF has protected glomerular mesangial cells from lipopolysaccharide-induced inflammation by inhibiting expressions of IL6, TNF-α, and AKT1, and activating expressions of VEGFA. Based on network pharmacology, we explored the multi-component, multi-target, and multi-pathway characteristics of JQHF in treating CGN, and found that JQHF could act on IL6, TNF-α, VEGFA, and AKT1 to exert the effect of anti-CGN, which provided new ideas and methods for further research on the mechanism of JQHF in treating CGN.

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Exclusive expression of transmembrane TNF aggravates acute glomerulonephritis despite reduced leukocyte infiltration and inflammation

Cited by 12 publications

References 52 publications

Metformin improves renal injury of MRL/lpr lupus-prone mice via the AMPK/STAT3 pathway

Metformin improves renal injury of MRL/lpr lupus-prone mice via the AMPK/STAT3 pathway

Identification of Taohong Siwu Decoction in Treating Chronic Glomerulonephritis Using Network Pharmacology and Molecular Docking

Exploring the mechanism of Jianpi Qushi Huayu Formula in the treatment of chronic glomerulonephritis based on network pharmacology

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