NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway

Li, Quanwei; Liao, Jianzhao; Chen, Weijin; Zhang, Kai; Li, Hongji; Ma, Feiyang; Zhang, Hui; Han, Qing; Guo, Jianying; Liu, Ying; Hu, Lianmei; Pan, Jiang; Tang, Zhaoxin

doi:10.1016/j.freeradbiomed.2022.05.024

“…Therefore, as a ferroptosis regulator, GPX4 could provide a potential strategy for DKD prognosis assessment as a ferroptosis regulator. Moreover, some chemical compounds including glabridin [52], N-acetylcysteine [53], and platycodin D [54] could also significantly alleviate ferroptosis in DKD via maintaining redox homeostasis through activating GPX4, which may be inspiring for clinical treatment. 7 Oxidative Medicine and Cellular Longevity Nuclear factor erythroid 2-related factor 2 (NRF2) was a transcription factor of various antioxidant genes including GPX4, and it is known to suppress oxidative stress and ferroptosis [55][56][57].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, as a ferroptosis regulator, GPX4 could provide a potential strategy for DKD prognosis assessment as a ferroptosis regulator. Moreover, some chemical compounds including glabridin [ 52 ], N-acetylcysteine [ 53 ], and platycodin D [ 54 ] could also significantly alleviate ferroptosis in DKD via maintaining redox homeostasis through activating GPX4, which may be inspiring for clinical treatment.…”

Section: Discussionmentioning

confidence: 99%

Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

Wang

¹

,

Chang

²

,

Zhao

³

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Diabetic kidney disease (DKD) represents a heavy burden in type 2 diabetes mellitus (T2DM). Ferroptosis plays an important role in DKD, and it thus provides new perspectives to pursue more related biomarkers to assess the disease severity and prognosis. Glutathione peroxidase 4 (GPX4) is the mainstay in regulating ferroptosis. The current study investigated the predictive value of kidney GPX4 expression level in DKD progression. Methods. We measured GPX4 levels in kidney paraffin sections of 85 biopsy-proven DKD patients by immunohistochemistry staining. The associations between the GPX4 level and clinicopathological parameters as well as renal outcomes were analyzed. Results. GPX4 is mainly expressed in kidney tubulointerstitium, especially in tubular epithelial cells of DKD patients. The GPX4 expression level was significantly lower in DKD patients than healthy controls. Besides, GPX4 level significantly correlated with proteinuria ( r = − 0.42 , p < 0.001 ), urinary albumin-to-creatinine ratio (uACR) ( r = − 0.40 , p < 0.01 ), serum creatinine (Scr) ( r = − 0.59 , p < 0.001 ), estimated glomerular filtration rate (eGFR) ( r = 0.66 , p < 0.001 ), and the percentage of sclerosed glomeruli ( r = − 0.42 , p < 0.001 ) in renal specimens. During follow-up, the GPX4 level positively correlated with eGFR slope ( r = 0.48 , p < 0.001 ), and GPX4-low patients showed a significantly higher probability of developing end-stage kidney disease (ESKD) compared with GPX4-high patients ( p < 0.01 ). Moreover, after adjusting for other potential predictors, the GPX4 level was still an independent predictor of developing ESKD (HR 2.15, 95% CI 1.08 to 4.28, p < 0.05 ). Conclusions. Kidney tubulointerstitial GPX4 expression level was associated with the disease severity and progression of DKD.

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“…Moreover, the decrease in GPX4 exacerbates ferroptosis in UC as evidenced by reduced GSH and increased malondialdehyde and lactate dehydrogenase [12], and the activation of GPX4 induced by Shaoyao decoction represses ferroptosis in ECs and promotes the repair of barrier function [47]. FIN56 is a potent agent that can induce ferroptosis by increasing GPX4 degradation [48][49][50]. Among the same type of inducers, the rationale of FIN56 to induce ferroptosis is similar to that of RSL3 [51], but differs from that of Erastin, which initiates ferroptosis by accelerating oxidation by voltage-dependent anion channels [52].…”

Section: Discussionmentioning

confidence: 99%

Promotive role of IRF7 in ferroptosis of colonic epithelial cells in ulcerative colitis by the miR-375-3p/SLC11A2 axis

Gu

¹

,

Chen

²

2022

Bosn J of Basic Med Sci

2

0

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Ferroptosis is implicated in the progression of ulcerative colitis (UC), and interferon regulatory factor 7 (IRF7) contributes to cell death. This study probed the mechanism of IRF7 in ferroptosis of colonic epithelial cells (ECs) in mice with dextran sodium sulfate (DSS)-induced UC. The UC mouse model and the in vitro ferroptosis model were respectively established by DSS feeding and the treatment of FIN56 (a ferroptosis inducer). Results of quantitative real-time polymerase chain reaction and western blotting revealed the upregulation of IRF7 and solute carrier family 11 member 2 (SLC11A2/NRAMP2/DMT1) and the downregulation of microRNA (miR)-375-3p in DSS-treated mice and FIN56-treated ECs. Silencing of IRF7 improved the symptoms of UC in DSS-induced mice and decreased the levels of tumor necrosis factor α, interleukin 6, monocyte chemoattractant protein 1, and interleukin 1β, reactive oxygen species, iron ions, lipid peroxidation, and increased glutathione and glutathione peroxidase 4. Chromatin immunoprecipitation and dual-luciferase assays showed that binding of IRF7 to the miR-375-3p promoter inhibited miR-375-3p expression, and miR-375-3p suppressed SLC11A2 transcription. The rescue experiments revealed that knockdown of miR-375-3p neutralized the role of silencing IRF7 in alleviating ferroptosis of colonic ECs. Overall, IRF7 upregulated SLC11A2 transcription by inhibiting miR-375-3p expression, thereby prompting ferroptosis of colonic ECs and UC progression in DSS-treated mice.

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“…Sirtuin3 (SIRT3) is a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that can effectively prevent the development of DN, whether by regulating the AMPK/SIRT3 signaling pathway or the SIRT3/SOD2 signaling pathway (Liu et al, 2019d;Guan et al, 2021;Wongmekiat et al, 2021;Li et al, 2022a). Under HG conditions, the expression of SIRT3 was inhibited in HK-2 cells, and glycolysis was abnormally altered, ultimately leading to EMT (Li et al, 2020c) In addition to regulating the process of renal fibrosis, SIRT3 has also been found to regulate the activation of inflammasomes.…”

Section: Epithelial-to-mesenchymal Transition and Endothelial-to-mese...mentioning

confidence: 99%

NLRP3-mediated pyroptosis in diabetic nephropathy

Wan

¹

,

Li

²

,

Pan

³

et al. 2022

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Diabetic nephropathy (DN) is the main cause of end-stage renal disease (ESRD), which is characterized by a series of abnormal changes such as glomerulosclerosis, podocyte loss, renal tubular atrophy and excessive deposition of extracellular matrix. Simultaneously, the occurrence of inflammatory reaction can promote the aggravation of DN-induced kidney injury. The most important processes in the canonical inflammasome pathway are inflammasome activation and membrane pore formation mediated by gasdermin family. Converging studies shows that pyroptosis can occur in renal intrinsic cells and participate in the development of DN, and its activation mechanism involves a variety of signaling pathways. Meanwhile, the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome can not only lead to the occurrence of inflammatory response, but also induce pyroptosis. In addition, a number of drugs targeting pyroptosis-associated proteins have been shown to have potential for treating DN. Consequently, the pathogenesis of pyroptosis and several possible activation pathways of NLRP3 inflammasome were reviewed, and the potential drugs used to treat pyroptosis in DN were summarized in this review. Although relevant studies are still not thorough and comprehensive, these findings still have certain reference value for the understanding, treatment and prognosis of DN.

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NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway

Cited by 96 publications

References 49 publications

Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

Glutathione Peroxidase 4 Is a Predictor of Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus

Promotive role of IRF7 in ferroptosis of colonic epithelial cells in ulcerative colitis by the miR-375-3p/SLC11A2 axis

NLRP3-mediated pyroptosis in diabetic nephropathy

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