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TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy.

ABSTRACT: OBJECTIVE AND DESIGN:Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor ?-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN. METHODS:TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) and lentiviral vector-mediated TAB1 knockdown was used in streptozotocin (STZ)-induced diabetic mice. Western blotting, flow cytometry, qRT-PCR, ELISA, PAS staining and immunohistochemical staining were used for assessment of TAB1/nuclear factor-?B (NF-?B)/hypoxia-inducible factor-1? (HIF-1?), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy. RESULTS:We found that TAB1/NF-?B/HIF-1?, iNOS and glycolysis were up-regulated in BMMs under HG conditions, leading to release of further inflammatory factors, Downregulation of TAB1 could inhibit glycolysis/polarization of macrophages and inflammation in vivo and in vitro. Furthermore, albuminuria, the tubulointerstitial damage index and glomerular mesangial expansion index of STZ-induced diabetic nephropathy mice were decreased by TAB1 knockdown. CONCLUSIONS:Our results suggest that the TAB1/NF-?B/HIF-1? signaling pathway regulates glycolysis and activation of macrophages in DN.

SUBMITTER: Zeng H

PROVIDER: S-EPMC7658079 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy.

Zeng Hanxu H Qi Xiangming X Xu Xingxin X Wu Yonggui Y

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 20201012 12

<h4>Objective and design</h4>Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN.<h4>Methods</h4>TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) a ...[more]

PMID: 33044562

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Project description:Validation of predicted gene expression of human mesangial cells after 24h Tacrolimus stimulus Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies. comparison of gene expression of human mesangial cells after 24h Tacrolimus vs. Ctrl; 4 independent experiments were conducted (4xTacrolimus 24h and 4x ctrl. 24h with Drug solvent (DMSO))

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TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy.

Publications

TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy.

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