Research progress on damage-associated molecular patterns in acute kidney injury

Abstract

Acute kidney injury (AKI) is a clinical syndrome characterized by a sudden dysfunction of the kidney, which is common worldwide, with a relatively high incidence and mortality rate. Damage to the proximal renal tubule is a pathological hallmark of AKI, and inflammation triggered by the overactivation of the immune system is a common cause of proximal renal tubular injury, which is an important contributing factor in AKI exacerbation. Damage-associated molecular patterns (DAMPs) are endogenous molecules released by cells in response to external stimuli that can trigger an inflammatory response by binding to specific pattern recognition receptors (PRRs). Numerous studies have indicated that when the kidney is exposed to external stress or chemical stimuli, injured cells actively secrete or passively release various DAMPs, which can exacerbate or attenuate kidney injury by stimulating or inhibiting the inflammatory response through binding to the appropriate receptor. Currently, there is a lack of early diagnostic biomarkers and specific therapeutic strategies for AKI in the clinic have been established, and given the important role of the release of DAMPs in the regulation of inflammatory response, they will highly likely become favorable candidate biomarkers and clinical therapeutic targets for AKI. Therefore, a deeper understanding of the types of DAMPs and the specific mechanisms of their actions will provide more possibilities for the specific AKI diagnosis and treatment.

Keywords: AKI; DAMPs; PRRs; immunity; inflammation.

Figure 1

Overview of the specific functions of DAMPs in AKI through binding to different PRRs (a) HMGB1 activates RAGE, leading to downstream NF-κB signaling and inflammatory factor release. (b) Most DAMPs such as HMGB1, histones, uric acid, mtDNA, uromodulin, biglycan, LMW-HA, and S100A8/A9 activate TLR2/4/9, exacerbating the inflammatory signaling cascade. Only the downstream canonical MyD88/NF-κB signaling pathway is shown. (c) ATP regulates NLRP3 inflammasome signaling through the activation of P2X7R and subsequently promotes inflammatory responses. (d) IL-1α activates IL-1R, promoting NF-κB translocation to the nucleus and activating inflammatory signaling. (e) IL-33 activates ST2, which promotes polarization of M2 macrophages and induces the expansion of ILC2s and Tregs to fight inflammation. Meanwhile, IL-33 binds to ST2 on the surface of iNKT cells, amplifying inflammatory injury. IL-33 exhibits dual functions, which may depend on the specific immune microenvironment. Footnote: Figure 1 only shows the function of IL-1α and IL-33 as DAMPs rather their function as secreted cytokines.