FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy

Xu, Xiaohong; Zhang, Liexiang; Fang, Hua; Zhang, Ce; Zhang, Chi; Xia, M.; Qin, Nan; Wang, Junsheng; Zhu, Aimin; Qin, Zihan; Zhou, Fangjian

doi:10.1016/j.yexcr.2021.112863

Cited by 32 publications

(20 citation statements)

References 43 publications

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“…Calorie restriction and exercise-mediated weight loss decreased mRNA levels of NLRP3 and IL-1β, and improved insulin sensitivity in diabetic subjects [ 33 ], demonstrating that pyroptosis contributes to the pathogenesis of IR and diabetes by mediating inflammation and β-cell destruction. The regulation of SIRT2, SIRT3, and SIRT4 expression is known to relate to inflammation and pyroptosis cell death [ 34 , 35 , 36 ]. To date, the concept of endothelial IR has not been clinically established because only a small number of clinical studies have shown the actual response to insulin in endothelial cells of patients with metabolic disorders [ 37 , 38 , 39 , 40 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

et al. 2022

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Emerging evidence indicates that defects in sirtuin signaling contribute to impaired glucose and lipid metabolism, resulting in insulin resistance (IR) and endothelial dysfunction. Here, we examined the effects of palmitic acid (PA) treatment on mitochondrial sirtuins (SIRT2, SIRT3, SIRT4, and SIRT5) and oxidative homeostasis in human endothelial cells (TeloHAEC). Results showed that treatment for 48 h with PA (0.5 mM) impaired cell viability, induced loss of insulin signaling, imbalanced the oxidative status (p < 0.001), and caused negative modulation of sirtuin protein and mRNA expression, with a predominant effect on SIRT3 (p < 0.001). Restoration of SIRT3 levels by mimic transfection (SIRT3+) suppressed the PA-induced autophagy (mimic NC+PA) (p < 0.01), inflammation, and pyroptosis (p < 0.01) mediated by the NLRP3/caspase-1 axis. Moreover, the unbalanced endothelial redox state induced by PA was counteracted by the antioxidant δ-valerobetaine (δVB), which was able to upregulate protein and mRNA expression of sirtuins, reduce reactive oxygen species (ROS) accumulation, and decrease cell death. Overall, results support the central role of SIRT3 in maintaining the endothelial redox homeostasis under IR and unveil the potential of the antioxidant δVB in enhancing the defense against IR-related injuries.

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Section: Discussionmentioning

confidence: 99%

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

et al. 2022

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“…NFκB, a transcription factor found in B lymphocyte precursor cells [ 53 ], is closely related to the production of various inflammatory cytokines and the regulation of inflammatory response in the body [ 54 ], and participates in multiple biological processes [ 53 , 54 ]. In mouse models of DN, researchers have found that NFκB was significantly activated in renal proximal tubule cells [ 55 , 56 ] and renal cortex tissue of the kidney [ 57 ]. In addition, proteinuria can also stimulate the activation of renal NFκB, which is one of the important pro-inflammatory stimuli in renal tubular cells [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Diphenyl Diselenide Alleviates Tert-Butyl Hydrogen Peroxide-Induced Oxidative Stress and Lipopolysaccharide-Induced Inflammation in Rat Glomerular Mesangial Cells

Wang

Huan

Liu

et al. 2022

IJMS

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Hyperglycemia, oxidative stress, and inflammation play key roles in the onset and development of diabetic complications such as diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple organic selenium compound with anti-hyperglycemic, anti-inflammatory, and anti-oxidative activities. Nevertheless, in vitro, the role and molecular mechanism of DPDS on DN remains unknown. Therefore, we investigated the effects of DPDS on tert-butyl hydrogen peroxide (t-BHP)-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation in rat glomerular mesangial (HBZY-1) cells and explored the underlying mechanisms. DPDS attenuated t-BHP-induced cytotoxicity, concurrent with decreased intracellular ROS and MDA contents and increased SOD activity and GSH content. Moreover, DPDS augmented the protein and mRNA expression of Nrf2, HO-1, NQO1, and GCLC in t-BHP-stimulated HBZY-1 cells. In addition, DPDS suppressed LPS-induced elevations of intracellular content and mRNA expression of interleukin (IL)-6, IL-1β and TNF-α. Furthermore, LPS-induced NFκB activation and high phosphorylation of JNK and ERK1/2 were markedly suppressed by DPDS in HBZY-1 cells. In summary, these data demonstrated that DPDS improves t-BHP-induced oxidative stress by activating the Nrf2/Keap1 pathway, and also improves LPS-induced inflammation via inhibition of the NFκB/MAPK pathways in HBZY-1 cells, suggesting that DPDS has the potential to be developed as a candidate for the prevention and treatment of DN.

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“…Several studies have since illustrated the widespread impact of NLRP3 inflammasome activation in diabetic nephropathy through its role in glomerular injury ( Xu et al, 2021 ; Zhan et al, 2020 ; Shen et al,2022 ; Feng et al, 2021 ). Research by Wu et al , studied the effects of NLRP3 in the kidneys of streptozotocin (STZ)-induced diabetic mice using an NLRP3 knock-out model ( Wu et al, 2018 ).…”

Section: The Nlrp3 Inflammasomementioning

confidence: 99%

“…One of several mechanisms through which NLRP3 drives glomerular disease is through increased pyroptosis ( Zhan et al, 2020 ; Xu et al, 2021 ), a form of programmed cell death stimulated by inflammation ( Lin et al, 2020 ). Renal tissue from high fat diet (HFD)/STZ-treated mice exhibited mitochondrial swelling, perforation and dissolution of the cell membrane, small vacuole formation on the cell surface and nuclear rupture, characteristics associated with pyroptosis ( An et al, 2020 ).…”

Section: The Nlrp3 Inflammasomementioning

confidence: 99%

The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy

et al. 2022

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The NOD-like receptor protein 3 (NLRP3) inflammasome is a multi-protein signalling complex integral to the chronic inflammatory response, activated in response to sterile and non-sterile cellular damage. The assembly and activation of the NLRP3 inflammasome comprise a two-step process involving nuclear factor kappa B (NFkB)-mediated priming, followed by canonical, non-canonical or alternative signalling pathways. These result in the maturation and release of inflammatory cytokines interleukin 1 beta (IL1ß) and interleukin-18 (IL18), which are associated with chronic inflammatory conditions including diabetic kidney disease. Diabetic nephropathy is a condition affecting ∼40% of people with diabetes, the key underlying pathology of which is tubulointerstitial inflammation and fibrosis. There is growing evidence to suggest the involvement of the NLRP3 inflammasome in this chronic inflammation. Early deterioration of kidney function begins in the glomerulus, with tubular inflammation dictating the progression of late-stage disease. Priming and activation of the NLRP3 inflammasome have been linked to several clinical markers of nephropathy including proteinuria and albuminuria, in addition to morphological changes including mesangial expansion. Treatment options for diabetic nephropathy are limited, and research that examines the impact of directly targeting the NLRP3 inflammasome, or associated downstream components are beginning to gain favour, with several agents currently in clinical trials. This review will explore a role for NLRP3 inflammasome activation and signalling in mediating inflammation in diabetic nephropathy, specifically in the glomerulus and proximal tubule, before briefly describing the current position of therapeutic research in this field.

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FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy

Cited by 32 publications

References 43 publications

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

Diphenyl Diselenide Alleviates Tert-Butyl Hydrogen Peroxide-Induced Oxidative Stress and Lipopolysaccharide-Induced Inflammation in Rat Glomerular Mesangial Cells

The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy

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