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 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.

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

“…A recent investigation has indicated that genes such as GPIHBP1 [ 123 ], FGFRL1 [ 124 ], DAPK2 [ 125 ], MAP 3K5 [ 126 ], ANKK1 [ 127 ], GK (glycerol kinase) [ 128 ], SPHK1 [ 129 ], GNG3 [ 130 ], FSTL3 [ 131 ], SLIT2 [ 132 ], CCDC80 [ 133 ], RND3 [ 134 ], PTGER4 [ 135 ], RUNX1 [ 136 ], ADAM12 [ 137 ], OLR1 [ 138 ], THBS1 [ 139 ], CD28 [ 140 ], TRPV4 [ 141 ], ATRN (attractin) [ 142 ], MRC1 [ 143 ], SEMA3C [ 144 ], HTR2B [ 145 ], NOX4 [ 146 ], TACR1 [ 147 ], BAMBI [ 148 ], PDGFD (platelet derived growth factor D) [ 149 ], APLN (apelin) [ 150 ], MFAP5 [ 151 ] and LUM (lumican) [ 152 ] are associated with a development of obesity. A previous investigation found that genes such asDDR1 [ 153 ], TAB1 [ 154 ], NEK8 [ 155 ], SERPINE2 [ 156 ], FCGR2B [ 157 ], ANGPT2 [ 158 ], FN1 [ 159 ], SOCS5 [ 158 ], SMOC2 [ 160 ], CD2 [ 161 ] and SCN9A [ 162 ] expression were associated with a kidney diseases, but these genes might be responsible for advancement of obesity associated type 2 diabetes mellitus.…”

Advances in understanding the innate immune‐associated diabetic kidney disease

“…75 Silencing of TGF-β-activated kinase 1 and triggering receptor expressed on myeloid cell 1 impeded polarization of macrophages into M1 phenotype, which conferred reduced renal inflammation in vitro and in vivo. 76,77 Mesangial stem cells alleviated inflammatory response and ameliorated renal injuries in diabetic mice by eliciting M2 macrophages via the stimulation of the transcription factor EB and restoration of lysosomal activity and autophagy in macrophages. 78 The treatment of diabetic mice with fasudil decreased M1/M2 macrophage ratio and increased anti-inflammatory cytokines production in the kidney, which ultimately attenuated renal injury.…”

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules 

“…A recent investigation has indicated that GPIHBP1 [123], FGFRL1 [124], DAPK2 [125], MAP3K5 [126], ANKK1 [127], GK (glycerol kinase) [128], SPHK1 [129], GNG3 [130], FSTL3 [131], SLIT2 [132], CCDC80 [133], RND3 [134], PTGER4 [135], RUNX1 [136], ADAM12 [137], OLR1 [138], THBS1 [139], CD28 [140], TRPV4 [141], ATRN (attractin) [142], MRC1 [143], SEMA3C [144], HTR2B [145], NOX4 [146], TACR1 [147], BAMBI [148], PDGFD (platelet derived growth factor D) [149], APLN (apelin) [150], MFAP5 [151] and LUM (lumican) [152] are associated with a development of obesity. A previous investigation found that DDR1 [153], TAB1 [154], NEK8 [155], SERPINE2 [156], FCGR2B [157], ANGPT2 [158], FN1 [159], SOCS5 [158], SMOC2 [160], CD2 [161] and SCN9A [162] expression were associated with a kidney diseases, but these genes might be responsible for advancement of obesity associated type 2 diabetes mellitus.…”