Autophagy and Inflammation Regulation in Acute Kidney Injury

Abstract

Autophagy at an appropriate juncture in the cell cycle exerts protective effects in acute kidney injury (AKI), whereas abnormal autophagy may lead to cell death. Inflammatory response plays a pivotal role in the pathophysiological process of kidney injury and repair during AKI. Several studies have reported an interaction between autophagy and inflammation in the pathogenesis of AKI. This review outlines recent advances in the investigation of the role of autophagy in inflammatory response regulation based on the following aspects. (1) Autophagy inhibits inflammatory responses induced in AKI through the regulation of mTOR and AMPK pathways and the inhibition of inflammasomes activation. (2) Autophagy can also help in the regulation of inflammatory responses through the nuclear factor kappa B pathway, which is beneficial to the recovery of kidney tissues. These studies reviewed here provide better insight into the mechanisms underlying the protective effects of the autophagy-inflammatory pathway. Through this review, we suggest that the autophagy-inflammatory pathway may serve as an alternative target for the treatment of AKI.

Keywords: acute kidney injury; autophagy; immune cells; inflammatory; tubular epithelial cells.

Figure 1

Induction and signaling pathways in autophagy. Autophagy is induced under conditions of nutrient starvation and stress by the activation of AMPK and suppression of the mTOR pathways. The initiation of autophagy is regulated by ULK1/2 complex phosphorylation of the VPS34–Beclin-1 complex, which leads to the recruitment of the cellular PI3P effector proteins DECP1 and WIPI 1/2 and contributes to the formation of an isolated membrane. Autophagosome formation requires the participation of two ubiquitin-like conjugation systems: the ATG12–ATG5–ATG16 complex, which promotes phagophore extension, and LC3/PE, which promotes phagophore closure. After autophagosomes are formed, they fuse with lysosomes and degrade the contents. AMPK: AMP-activated protein kinase; PI3P: phosphatidylinositol-3-phosphate; DECP1: protein 1 containing zinc finger FYVE domain; WIPI 1/2: WD-repeat domain phosphoinositide interaction protein; LC3: light chain 3; VPS34: vacuolar protein sorting 34; PE: phosphatidylethanolamine; ULK1: Unc-51-like kinase 1.

Figure 2

Autophagy and inflammatory response during acute kidney injury (AKI). Renal dysfunction during AKI may result from the external or internal signals involving PRRs, chemokines, cytokines, and ROS. Autophagy can elicit a dynamic response to inflammation. Active autophagy prevents an excessive inflammatory response by preventing the inflammasome activation, mediating the clearance of DAMPs and damaged mitochondria, and degrading inflammatory mediators. DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptors; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa b; ROS, reactive oxygen species; TLRs, membrane-associated toll-like receptors.

Figure 3

Autophagy and inflammation regulation and outcomes in AKI. Both infectious and noninfectious processes can trigger an inflammatory response, following which parenchymal cells and immune cells can induce AKI, which, in turn, lead to influx of innate immune cells, mainly macrophages, neutrophils, and natural killer (NK) T cells. Both cells of the innate immune system and adaptive immune effector cells are responsible for subsequent damage (Th2 cells plasma B cells) and repair (Th1 and Treg cells, M2 macrophages).