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.

Mitochondrial energetics in the kidney

“…In mice from which the genes encoding the autophagy regulators autophagy-related protein 7 (ATG7) and ATG5 were specifically knocked out in renal proximal tubules, mitochondrial dysfunction was greater in renal proximal tubules in response to IRI, as characterized by severe morphological changes, increased ROS production and apoptosis 167–169 . Activation of NIX and BNIP3 causes the release of ROS and the pro-apoptotic proteins BAX and BAK, in hypoxic conditions 116,170 . Deletion of BAX and BAK in mouse kidneys not only protected mice from ischaemic AKI but also suppressed mitochondrial fragmentation and the release of cytochrome c , preserving mitochondrial integrity 171 .…”

Oxidative Stress and Acute Kidney Injury in Critical Illness: Pathophysiologic Mechanisms—Biomarkers—Interventions, and Future Perspectives

“…It is generally described as a “housekeeping” process and aims at the removal of damaged and dysfunctional molecules as well as at the enhanced response to acute situations such as nutrient deficiency, ensuring the recycling of components for protein and energy synthesis and the elimination of toxic material [40]. Fundamental for the initiation of autophagy is the expression of the autophagy-related genes (ATG) that were first discovered in yeast, with the produced proteins being subjected to multiple posttranslational modifications that regulate the final outcome [41].…”

“…The first step is the formation of an intracellular, double-membrane organelle called phagophore that after the sequestration of the target turns into autophagosome and with the subsequent lysosomal fusion becomes the autolysosome that with the intermediary action of lysosomal enzymes will lead to the degradation of the contained cytoplasmic components in order to provide matrix for “recycling” [44]. The process is complete after lysosomal reformation and the inhibitory effect on autophagy of mammalian target of rapamycin receptor (mTOR) [39, 40]. Nevertheless, there are pending issues regarding the further clarification of the complicated signaling pathways in autophagy, their selectivity, and regulation [39].…”

The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

“…Mitochondrial damage characteristic with membrane permeability transition, ROS production and insufficient mitophagy corporately leads to mtDNA secretion, which exerts potent activation effect on inflammation response [12, 47, 52]. The increased mtDNA in circulation shows the extent of tissue injury, triggering a vicious cycle that inflammation induces mtDNA damage and secretion, then increased mtDNA in turn amplifies inflammation response and tissue injury [17, 53].…”