Epigenetic dysregulation of autophagy in sepsis-induced acute kidney injury: the underlying mechanisms for renoprotection

Abstract

Sepsis-induced acute kidney injury (SI-AKI), a common critically ill, represents one of the leading causes of global death. Emerging evidence reveals autophagy as a pivotal modulator of SI-AKI. Autophagy affects the cellular processes of renal lesions, including cell death, inflammation, and immune responses. Herein, we conducted a systematic and comprehensive review on the topic of the proposed roles of autophagy in SI-AKI. Forty-one relevant studies were finally included and further summarized and analyzed. This review revealed that a majority of included studies (24/41, 58.5%) showed an elevation of the autophagy level during SI-AKI, while 22% and 19.5% of the included studies reported an inhibition and an elevation at the early stage but a declination of renal autophagy in SI-AKI, respectively. Multiple intracellular signaling molecules and pathways targeting autophagy (e.g. mTOR, non-coding RNA, Sirtuins family, mitophagy, AMPK, ROS, NF-Kb, and Parkin) involved in the process of SI-AKI, exerting multiple biological effects on the kidney. Multiple treatment modalities (e.g. small molecule inhibitors, temsirolimus, rapamycin, polydatin, ascorbate, recombinant human erythropoietin, stem cells, Procyanidin B2, and dexmedetomidine) have been found to improve renal function, which may be attributed to the elevation of the autophagy level in SI-AKI. Though the exact roles of autophagy in SI-AKI have not been well elucidated, it may be implicated in preventing SI-AKI through various molecular pathways. Targeting the autophagy-associated proteins and pathways may hint towards a new prospective in the treatment of critically ill patients with SI-AKI, but more preclinical studies are still warranted to validate this hypothesis.

Sepsis-Associated Acute Kidney Injury: Where Are We Now?

“…Most studies are in agreement with the notion that autophagy rises early in the development of SA-AKI and falls afterward [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Moreover, autophagy has been proposed to be a key player in SA-AKI therapeutics and could serve as a major target for SA-AKI prevention and treatment [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Apart from autophagy, another process called “efferocytosis” could also be involved in SA-AKI.…”

“…In this complicated procedure, which is lysosome-dependent, a significant number of signaling molecules are implicated. Although the exact mechanisms are not yet completely understood, there seems to be an interplay between the mTOR (mammalian target of the rapamycin), sirtuins, especially sirtuins 1, 3 and 6, and NF- κ B (nuclear factor kappa B) [ 31 , 32 , 33 ]. As a result of cellular stress, autophagy is being regulated by autophagy-related genes (ATG), such as Atg5 and Atg7 , which have already been documented to be involved in the development of kidney disease [ 34 , 35 ].…”

“…As a result of cellular stress, autophagy is being regulated by autophagy-related genes (ATG), such as Atg5 and Atg7 , which have already been documented to be involved in the development of kidney disease [ 34 , 35 ]. In addition, Zhao et al have already proposed the complex interplay between ATG and the mTOR, sirtuins 1, 3 and 6, and the NF- κ B signaling pathways in SA-AKI [ 32 ]. Autophagy may play a crucial role in the pathogenesis of SA-AKI [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

“…In addition, Zhao et al have already proposed the complex interplay between ATG and the mTOR, sirtuins 1, 3 and 6, and the NF- κ B signaling pathways in SA-AKI [ 32 ]. Autophagy may play a crucial role in the pathogenesis of SA-AKI [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Most studies are in agreement with the notion that autophagy rises early in the development of SA-AKI and falls afterward [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

“…Autophagy may play a crucial role in the pathogenesis of SA-AKI [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Most studies are in agreement with the notion that autophagy rises early in the development of SA-AKI and falls afterward [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Moreover, autophagy has been proposed to be a key player in SA-AKI therapeutics and could serve as a major target for SA-AKI prevention and treatment [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”