Sirtuin 3 deficiency aggravates contrast-induced acute kidney injury

Zhang, Qinghai; Liu, Xun; Li, Na; Zhang, Jihong; Yang, Jianmin; Bu, Peili

doi:10.1186/s12967-018-1690-5

Cited by 33 publications

(26 citation statements)

References 23 publications

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“…The reduction of systemic inflammation through inhibition of proinflammatory activation of circulating immune cells allows the system to break from the vicious cycle that perpetuates the disease. Mechanistically, NAD + repletion by NR has been shown to reduce mtROS production across tissue types (15,(43)(44)(45)(46), which suppresses NLRP3 inflammasome/caspase I axis and secretions of active IL-1B and IL-18 ( Figure 5 and ref. 28).…”

Section: Discussionmentioning

confidence: 99%

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Zhou¹,

Wang

Qiu³

et al. 2020

Journal of Clinical Investigation

151

100

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BACKGROUND. While mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level. METHODS. We compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor. RESULTS. We demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF. CONCLUSION. These findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF. TRIAL REGISTRATION. ClinicalTrials.gov NCT03727646.

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Section: Discussionmentioning

confidence: 99%

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Zhou¹,

Wang

Qiu³

et al. 2020

Journal of Clinical Investigation

151

100

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“…In a murine model of cisplatin-induced acute kidney injury, increased oxidative stress was associated with a reduced level of Sir3 and mitochondrial damage [30]. A recent study showed that ioversol treatment significantly increased the Sirt3 expression in wild-type (WT) mice and HK-2 cells, while Sirt3 deficiency aggravated the contrast-induced acute kidney injury [31]. Although there are scant reports on the role of Sirt3 in contrast-induced AKI, the molecular mechanism of its activation remains unknown.…”

Section: Discussionmentioning

confidence: 99%

tert-Butylhydroquinone Treatment Alleviates Contrast-Induced Nephropathy in Rats by Activating the Nrf2/Sirt3/SOD2 Signaling Pathway

Zhou

Wang

Shao

et al. 2019

Oxidative Medicine and Cellular Longevity

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Oxidative stress plays a critical role in the pathophysiology of contrast-induced nephropathy (CIN). Since the specific treatment of CIN remains an unmet medical need, it is imperative to find an effective strategy against the clinical management of CIN. The transcription factor Nrf2 is known to regulate antioxidative stress response. The aim of the present study was to assess the effects of tert-butylhydroquinone (t-BHQ), an activator of Nrf2, in the prevention of CIN and elucidate the underlying mechanism of its action in vitro and in vivo. We established a rat model of CIN and treated the animals with t-BHQ (25 mg/kg). The effects of t-BHQ treatment on CIN rats were elucidated by assessing renal function, HE staining, immunohistochemistry, and western blotting. We also studied the activity of oxidative stress-related markers, such as intracellular ROS level, MDA level, SOD2 activity, and GSH/GSSG ratio. We validated our results by siRNA-mediated silencing of Nrf2 in HK-2 cells exposed to the radiocontrast agent. Treatment with t-BHQ significantly ameliorated the renal function and the histopathological lesions in CIN rats. Further, pretreatment with t-BHQ significantly increased the SOD2 activity and GSH/GSSG ratio and decreased the levels of ROS and MDA in animals subjected to ioversol exposure. In addition, t-BHQ treatment increased the expression of Nrf2, Sirt3, and SOD2 and concomitantly decreased the expression of acetylated-SOD2. When Nrf2-silenced HK-2 cells were exposed to radiocontrast agent, they suffered severe cell oxidative stress, exhibited lower expression of Sirt3 and SOD2, and expressed higher levels of acetylated-SOD2; however, t-BHQ treatment did not affect the protein expression of these indicators in si-Nrf2 HK-2 cells. Our findings suggested that Nrf2 plays an important role in the regulation of the Sirt3/SOD2 antioxidative pathway, and t-BHQ may be a potential agent to ameliorate radiocontrast-induced nephropathy via activating the Nrf2/Sirt3/SOD2 signaling pathway in vitro and in vivo.

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“…The absence of SIRT3 expression will aggravate acute renal injury (AKI), and increase ROS levels and apoptosis. Activation of SIRT3 decreases the acetylation of CypD, thereby inhibiting mitochondrial damage of AKI, and thus protecting the kidneys 143 , 144 . Activation of SIRT3 also inhibits the acetylation of p53 which blocks apoptosis in AKI 145 .…”

Section: Sirt3 and Human Diseasementioning

confidence: 99%

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Zhang¹,

Xiang²,

Liu³

et al. 2020

Theranostics

289

238

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Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.

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Sirtuin 3 deficiency aggravates contrast-induced acute kidney injury

Cited by 33 publications

References 23 publications

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

tert-Butylhydroquinone Treatment Alleviates Contrast-Induced Nephropathy in Rats by Activating the Nrf2/Sirt3/SOD2 Signaling Pathway

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

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