Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury

Abstract

Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI) is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed.

Keywords: ischemia-reperfusion injury; kidney disease; nephrotoxicity; oxidative stress; tissue regeneration.

Figure 1

The pathophysiology of acute kidney injury involves renal tubules and vascular endothelium cell injury and inflammatory response. Diagram shows healthy tubule (right, unshaded) and injured tubule (left, shaded). The tubule cell damage involves different forms of cell death which result in loss of brush border (villi blebbing), loss of cell polarity (cytoskeletons), tubular obstruction, and cast formation. Peri-tubule vessel damage causes vascular endothelial dysfunction including: microvascular obstruction, vasoconstriction, vascular leakage, and edema. The accumulation of immune cells, such as NK cells, neutrophils, macrophages, and dendritic cells, at damaged tubules cause the release of inflammatory cytokines and further tubule cell injury. TBM, tubular basement membrane.

Figure 2

Inflammasome signaling acting in a two-step activation of IL-1β and IL-18. Activation of the NLPR3 inflammasome requires two signals. Signal 1 involves the activation of TLRs, IL-1R, IL-18R and TNFRs by DAMPs or PAMPs which then induces the transcriptional activation of NF-κB and subsequent production of pro-IL-1β and pro-IL-18; Signal 2 involves different pathways such as ion (K⁺) efflux, generation of ROS, ATP/P2X₇R activation and lysosomal rupture/release of the endogenous cathepsins into the cytosol. Both signals coordinately induce assembly of the inflammasome complex: NLRP3 (sensor), apoptosis-associated speck-like (adaptor) and recruitment and enzymatic cleavage/activation of active caspase-1. Activated caspase-1 cleaves pre-forms of pro-IL-1β and pro-IL-18 to release the pro-immunogenic IL-1β and IL-18. Solid arrows indicate direct activation; dashed arrows indicate indirect activation.

Figure 3

Autophagy contributes to protein degradation and damaged organelle removal in renal tubule cells. Active endocytosis occurs in the renal tubule cells for kidney ultrafiltrate reabsorption. Amphisome, a form of autophagic vacuole, is formed by fusion of an endosome with an autophagosome. Macroautophagy is triggered by the activation of an autophagic protein complex that induces LC3 recruitment to the nascent autophagosome (isolation membrane). Proteins that are committed for degradation are labeled by polyubiquitin chains and delivered to the autophagosome by the p62 scaffold protein. Fusion of autophagosomes and lysosomes, known as autolysosomes, results in the degradation of the contents. Selective autophagy like mitophagy and lysophagy are used to remove damaged mitochondria (depolarization of inner mitochondrial membrane) or ruptured lysosome, respectively, during tubule cell injury.