Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

Zhang, Yang; Wang, Ling; Meng, Liesu; Cao, Guangke; Yu, Wen-Ying

doi:10.1080/15384101.2019.1568746

Cited by 61 publications

(34 citation statements)

References 45 publications

(42 reference statements)

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“…We measured the activity of enzymes related to oxidative stress and the GSH levels, and we found a decrease in reduced GSH in both LPS groups. These data are in accordance with the literature ( Islam et al, 2019 ; Zhang et al, 2019 ). Nonetheless, the trained + LPS group showed a marked reduction of GSH compared to control, but with no differences between sedentary + LPS and trained + LPS groups.…”

Section: Discussionsupporting

confidence: 94%

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

et al. 2020

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Introduction: Lipopolysaccharide (LPS) is a systemic response-triggering endotoxin, which has the kidney as one of its first targets, thus causing acute injuries to this organ. Physical exercise is capable of promoting physiological alterations and modulating inflammatory responses in the infectious process through multiple parameters, including the toll-like receptor (TLR)-4 pathway, which is the main LPS signaling in sepsis. Additionally, previous studies have shown that physical exercise can be both a protector factor and an aggravating factor for some kidney diseases. This study aims at analyzing whether physical exercise before the induction of LPS endotoxemia can protect kidneys from acute kidney injury. Methods: C57BL/6J male mice, 12 weeks old, were distributed into four groups: (1) sedentary (control, N = 7); (2) sedentary + LPS ( N = 7); (3) trained ( N = 7); and (4) trained + LPS ( N = 7). In the training groups, the animals exercised 5×/week in a treadmill, 60 min/day, for 4 weeks (60% of max. velocity). Sepsis was induced in the training group by the application of a single dose of LPS (5 mg/kg i.p.). Sedentary animals received LPS on the same day, and the non-LPS groups received a saline solution instead. All animals were euthanized 24 h after the administration of LPS or saline. Results: The groups receiving LPS presented a significant increase in serum urea ( p < 0.0001) and creatinine ( p < 0.001) concentration and renal gene expression of inflammatory markers, such as tumor necrosis factor alpha and interleukin-6, as well as TLRs. In addition, LPS promoted a decrease in reduced glutathione. Compared to the sedentary + LPS group, trained + LPS showed overexpression of a gene related to kidney injury (NGAL, p < 0.01) and the protein levels of LPS receptor TLR-4 ( p < 0.01). Trained + LPS animals showed an expansion of the tubulointerstitial space in the kidney ( p < 0.05) and a decrease in the gene expression of hepatic AOAH ( p < 0.01), an enzyme involved in LPS clearance. Conclusion: In contrast to our hypothesis, training was unable to mitigate the renal inflammatory response caused by LPS. On the contrary, it seems to enhance injury by accentuating endotoxin-induced TLR-4 signaling. This effect could be partly due to the modulation of a hepatic enzyme that detoxifies LPS.

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Section: Discussionsupporting

confidence: 94%

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

et al. 2020

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“…The immunomodulatory function of most sirtuins has been shown to relieve sepsis-induced AKI. Overexpression of SIRT1 and SIRT6 was associated with alleviation of tubular injury induced by lipopolysaccharide treatment in an animal model of cecal ligation and puncture [ 96 , 97 ]. Similar results were obtained from sepsis-induced AKI model treated with resveratrol, a sirtuin activator [ 98 ].…”

Section: The Role Of Sirtuins In Renal Diseasementioning

confidence: 99%

The Role of Sirtuins in Kidney Diseases

Hong

Kim

et al. 2020

IJMS

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Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

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“…Overexpression of SIRT6 down-regulates LPS-induced TNF-α and IL-6 secretion, inhibits LPS-induced apoptosis, promotes autophagy in renal tubular epithelial cells (HK-2 cells), and repairs LPS-induced renal injury. Furthermore, silencing the SIRT6 gene not only promotes TNF-α and IL-6 secretion, but also promotes apoptosis and reduces autophagy in HK-2 cells (Zhang et al, 2019b). Therefore, we still believe that autophagy plays a protective role in septic AKIs, but more specific mechanisms need to be further clarified.…”

Section: Mechanism Of Action Of Autophagy In Different Organsmentioning

confidence: 99%

The Role of Autophagy in Sepsis: Protection and Injury to Organs

et al. 2019

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Sepsis is a systemic inflammatory disease with infection, and autophagy has been shown to play an important role in sepsis. This review summarizes the main regulatory mechanisms of autophagy in sepsis and its latest research. Recent studies have shown that autophagy can regulate innate immune processes and acquired immune processes, and the regulation of autophagy in different immune cells is different. Mitophagy can select damaged mitochondria and remove it to deal with oxidative stress damage. The process of mitophagy is regulated by other factors. Non-coding RNA is also an important factor in the regulation of autophagy. In addition, more and more studies in recent years have shown that autophagy plays different roles in different organs. It tends to be protective in the lungs, heart, kidneys, and brain, and tends to be damaging in skeletal muscle. We also mentioned that some drugs can regulate autophagy. The process of modulating autophagy through drug intervention appears to be a new potential hope for the treatment of sepsis.

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Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

Cited by 61 publications

References 45 publications

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

The Role of Sirtuins in Kidney Diseases

The Role of Autophagy in Sepsis: Protection and Injury to Organs

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