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. 2021 Jan 25;8:618536. doi: 10.3389/fcell.2020.618536

Figure 2.

Figure 2

miRNAs modulate monocyte/macrophage function to affect inflammation in DN. In the diabetic state, chronic hyperglycaemia activates NF-κB through multiple intracellular signaling pathways, such as ROS/NO, AGE-RAGE, the Hexo/Poly pathway, and the PKC pathway. Then, NF-κB moves into the nucleus to enhance the expression of several pro-inflammatory genes (TNF-α, IL-1β, IL-6, and IL-18). These pro-inflammatory cytokines contribute to M1 macrophage polarization and NLRP3 inflammasome activation, causing macrophage infiltration and renal inflammation. NF-κB binds to the 3′-UTR of miR-146a to promote its transactivation, and upon processing and maturation, miR-146a enters the cytoplasm and prevents the translation of IRAK1 and TRAF6 mRNAs. Both IRAK1 and TRAF6 activate IKKs, which in turn phosphorylate IκB to release NF-κB. Subsequently, the released NF-κB reduces inflammation to ameliorate diabetic renal inflammation. AGEs, advanced glycation end products; DN, diabetic nephropathy; Hexo/Poly, hexosamines and polyols; IKKs, IκB kinases; IRAK1, interleukin receptor associated kinase 1; NF-κB, nuclear factor kappa-B; NLRP3, NLR family pyrin domain containing 3; PKC, protein kinase C; RAGE, advanced glycation end products and its acceptor; ROS/NO, reactive oxygen species/nitric oxide; TNF-α, tumor necrosis factor-α; TRAF6, tumor necrosis factor receptor associated factor 6.