The Interplay of Renin‐Angiotensin System and Toll‐Like Receptor 4 in the Inflammation of Diabetic Nephropathy

Figures

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  Figure 1. TLRs and signaling molecules on the basis of literatures. The majority of TLRs seem to function as a homodimer, but TLR2 forms a heterodimer with TLR1 or TLR6. TLR signaling consists of two distinct pathways: the MyD88-dependent and MyD88-independent cascades. TLR4 can activate both MyD88-dependent and MyD88-independent pathways. TLR3 in the endosome recruits TRIF and mediates the MyD88-independent pathway. The engagement of TLR7, TLR8, and TLR9 in the endosome membrane leads to the formation of a complex that consists of MyD88 and IRAK. TLR2, TLR7, TLR8, and TLR9 can only activate MyD88-dependent pathway. LPS, lipopolysaccharides; dsRNA, double-stranded RNA; ssRNA, single-stranded RNA; TIRAP, TIR domain-containing adaptor protein/MyD88 adaptor-like protein; TIR, Toll-like/IL-1 receptor; TRAM, TRIF-related adaptor molecule; TRIF, TIR-domain-containing adaptor-inducing IFN-β; IRF3, interferon regulatory factor 3; IRAK, interleukin-1 receptor-associated kinase; TRAF6, tumor necrosis factor receptor- (TNFR-) associated factor 6; MAPK, mitogen-activated protein kinase; AP-1, activator protein 1; NF-κB, nuclear factor-κB; IFN-β, interferon-β.

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  Figure 2. TLR4 signaling pathway in the DN on the basis of literatures. Activation of TLR4 initiates the MyD88-dependent and MyD88-independent pathways. Moreover, the pathways converge in the activation of NF-κB, which is responsible for the synthesis and secretion of proinflammatory cytokines, chemokines, cell adhesion molecules, and profibrotic markers involved in inflammation and fibrosis, eventually leading to diabetic nephropathy. HSPs: heat shock proteins; HMGB1: high-mobility-group box 1.

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  Figure 3. Classical renin-angiotensin system (RAS) and the overview of RAS under pathological conditions of DN. (a) Components of classical RAS. (b) Schematic representation of RAS signaling cascades involve in the inflammation of DN. Ang: angiotensin; ACE: angiotensin-converting enzyme; AT1R: angiotensin II type 1 receptor; AT2R: angiotensin II type 2 receptor; PLC: phospholipase C; IP3, inositol triphosphate; DAG, diacylglycerol; PKC, protein kinase C; MAPKs: mitogen-activated protein kinases; NADPH: nicotinamide adenine dinucleotide phosphate; ROS: reactive oxygen species.

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  Figure 4. The possible cross-regulation of RAS and TLR4 in mediating the inflammation of DN. By binding to AT1R, Ang II upregulates TLR4 with consequent activation of MyD88/MAPK pathway, resulting in NF-κB activation as well as production of proinflammatory cytokines, chemokines, and profibrotic factors that contribute to diabetic nephropathy. In addition, activated TLR4/MyD88/MAPK signaling cascade enables to induce ACE and AT1 expression, Ang II production, and inflammation in DN.