TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy
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Inflammation Research
ORIGINAL RESEARCH PAPER
TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy Hanxu Zeng1 · Xiangming Qi1 · Xingxin Xu1 · Yonggui Wu1 Received: 26 February 2020 / Revised: 9 September 2020 / Accepted: 3 October 2020 © The Author(s) 2020
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 β-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-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy. Results We found that TAB1/NF-κB/HIF-1α, 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-κB/HIF-1α signaling pathway regulates glycolysis and activation of macrophages in DN. Keywords Diabetic nephropathy · Glucose metabolism · Macrophage · TAB1
Introduction It has been widely accepted that inflammation is central to the development of diabetic nephropathy (DN). This disorder of glucose control in diabetics can cause inflammation and cellular stress, causing functional deterioration seen in Responsible Editor: John Di Battista. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00011-020-01411-4) contains supplementary material, which is available to authorized users. * Xingxin Xu [email protected] * Yonggui Wu [email protected] 1
Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Rd., Hefei, Anhui, China
DN [1, 2]. Studies have shown that macrophage polarization occurs in renal inflammation and plays a decisive part in DN, and secretion of pro-inflammatory mediators by macrophages after activation contributes to deterioration of DN [3]. Macrophages are subdivided into two subpopulations: the classically-activated or M1 phenotype macrophages and the alternatively-activated or M2 macrophages. M1 phenotype macrophages are observed to deliver higher levels of pro-inflammatory cytokines to deal with infections [4, 5]. Macrophages can re
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