Figure 1.

TLR4 signalling in SI‐AKI. LPS binding to the extracellular domain of TLR4 and MD2 is facilitated by CD14 and results in activation of both the MyD88‐ and TRIF‐dependent pathways. In the proximal tubule, it has been described that upon activation the entire TLR4/MD2/CD14 complex is subject to endocytosis. The downstream effects include upregulation of transcription factors NFkB, AP‐1 and IRF‐3 resulting in transcription of pro‐inflammatory genes including cytokines, chemokines, adhesion molecules and interferons. Furthermore, activation of MAPKs such as p38, ERK and JNK takes place. The ensuing overall renal effects include endothelial and tubular dysfunction in addition to altered renal metabolism and circulation (not shown in figure), giving rise to acute kidney injury. The two methods of inhibiting TLR4 signalling are shown above. Eritoran (E5564), a synthetic lipopolysaccharide, binds to cell‐surface TLR4‐MD2 without activating the receptor and thus inhibits signalling by bacterial LPS. Resatorvid (TAK‐242) binds to TLR4's intracellular domain and blocks further signalling downstream. TRIF (Toll/IL‐1 receptor domain containing adaptor inducing IFN‐β); IRF‐3 (interferon regulatory factor 3); NFkB (nuclear factor kappa‐light‐chain enhancer of activated B cells); AP‐1 (activator protein 1); TRAF (TNF receptor associated factor); IRAK (impairment of IL‐1R associated kinase 1 activity); TAK1 (transforming growth factor beta‐activated kinase 1); TBK1 (tank binding kinase 1); IKK (I‐kappa B kinase complex); MAPKs (mitogen activated protein kinases).