Toll-Like Receptors in Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological condition.

Keywords: acute kidney injury; drugs; inflammation; therapy; toll-like receptors.

Figure 1

TLR4 signaling pathway. Upon ligand recognition, TLR4 forms homodimers and signals through MyD88-dependent and MyD88-independent pathways. In early phase of TLR4 activation, MyD88-dependent pathways begins with TIRAP and MyD88 recruitment to TLR4 and subsequently assembly with TRAF6, IRAK1 and IRAK4. TRAF6 associates with the complex formed by TAB1, TAB2, TAB3 and TAK1. Once activated, TAK1 mediates the phosphorylation of the IKK complex (IKKα, IKKβ, and IKKγ), which phosphorylates the inhibitory subunit IkB, resulting in nuclear NFκB translocation and proinflammatory genes expression. Besides activating NFκB, TAK1 also phosphorylates and activates MAP kinases (ERK, Jnk, p38) to further reinforce the proinflammatory cytokines expression. MyD88-independent pathway requires the recruitment of TRIF and TRAM to TLR4 after its internalization in endosomes. The subsequent association with RIP1 and TRAF6 converges in the activation pathway of NFκB in a late phase of TLR4 activation. TRAF3 activates IRF3 through IKKε and TBK1, inducing transcription of type I interferons and IFN-inducible genes. Created with BioRender.com.

Figure 2

TLR4 in the pathophysiology of AKI. Activation of TLR4 signaling pathway has been observed in different types of AKI. On the one hand, models that reduce renal blood flow generate an increase of TLR4 expression in endothelial, tubular and leukocyte cells. Endothelial dysfunction is a common mechanism in all types of AKI. This dysfunction leads to an increase in the expression of cell-adhesion molecules, activation of the innate immune response (neutrophils and macrophages) and the concomitant maintenance of oxidative stress. On the other hand, the presence and/or release of endo/exotoxins in some AKI, allows the development of endothelial dysfunction as well as activation of platelets and complement cascade, which obstruct glomerular blood flow, decreasing glomerular filtration rate. Other pathological changes detected in different types of AKI are largely observed in the tubulointerstitial space, mainly related to accumulation of toxins. The maintenance of a partial and/or total obstruction in the urinary tract, either by an exogenous (e.g., prostatic hyperplasia) or endogenous mechanism (e.g., detritus overload), produces an increase in luminal pressure, dilation of the collecting ducts, loss of functional units and development of tubulointerstial fibrosis. The pre-renal, intrarenal and post-renal manifestations are closely linked and the affection of one compartment has a direct impact on the others, enhancing the severity of AKI. Created with BioRender.com.

Figure 3

AKI-CKD Transition. There are multiple renal outcomes after AKI, from full recovery of renal function to chronic damage and permanent renal impairment. The lines on the graph represent the variation in glomerular filtration rate (GFR) during an AKI event, according the current definitions by KDIGO-AKI workgroup. The green and blue lines show a favorable scenario after an AKI event, with full recovery of renal damage and no evidence of CKD. An important difference between these lines is a better outcome in the case of an early improvement (<2 days, green line). The yellow line shows the persistence of acute/subacute kidney damage between the 7th and 90th day after the initial AKI event, currently called Acute Kidney Disease (AKD). The orange line shows an AKI event in the context of CKD. Patients suffering from AKI, in the presence of CKD, have a higher risk of progressing to chronic renal damage. The red line shows recurrent AKI events in absence of previous CKD. These multiple injury hits significantly reduce GFR over time. AKI episodes may be more intense or recurrent in genetically susceptible individuals and in the presence of other risk factors, including an established CKD. Growing evidence supports that TLR4-dependent pro-inflammatory/pro-fibrotic effects may play a key role in AKI-CKD transition. Created with BioRender.com.