Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation

Song, Jiayu; Wang, Hongri; Sheng, Jingyi; Zhang, Wen; Lei, Juan; Gan, Weihua; Cai, Fangfang; Yang, Yunwen

doi:10.1186/s10020-023-00735-1

Cited by 13 publications

(5 citation statements)

References 45 publications

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“…It has been reported that the Keap1/Nrf2 pathway participates in regulating several cellular processes, such as fibrosis 46 and autophagy. 44 Under physiological conditions, Nrf2 is produced and degraded, regulated by Keap1 via the pathway of ubiquitination, but under stress conditions, Nrf2 is released from Keap1 and enters the cell nucleus, which transactivates a large number of antioxidants, including HO-1.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-204-5p Ameliorates Renal Injury via Regulating Keap1/Nrf2 Pathway in Diabetic Kidney Disease

Dong,

Liu,

Bian

et al. 2024

DMSO

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Background Diabetic kidney disease (DKD) is characterized by renal fibrosis, and the pathogenesis of renal fibrosis is still not definitely confirmed. MiR-204-5p plays an important role in the regulation of fibrosis, autophagy and oxidative stress. In this study, we aimed to investigate the role of miR-204-5p on renal damage in diabetic kidneys and the underlying mechanisms involved. Methods In vivo, AAV-Ksp-miR-204-5p mimics were injected into mice via tail vein. In vitro, high glucose-induced HK-2 cells were treated with miR-204-5p inhibitor, miR-204-5p mimics, ATG5 siRNA, tertiary butyl hydroquinone (TBHQ), ML385, or 3-Methyladenine (3-MA). FISH and qRT-PCR were used to detect miR-204-5p expression. The expressions of protein and mRNA were detected by Western blotting, immunofluorescence, immunohistochemistry and qRT-PCR. The concentration of fibronectin in HK-2 cells culture medium was detected by ELISA. Results The expression of miR-204-5p in diabetic kidneys was significantly inhibited than that in control group. Delivering miR-204-5p mimics increased miR-204-5p expression, improved renal function, inhibited renal fibrosis and oxidative stress, and restored autophagy in db/db mice. In vitro, the expression of miR-204-5p was inhibited by HG treatment in HK-2 cells. MiR-204-5p mimics effectively increased miR-204-5p expression and reduced fibronectin and collagen I expression, restored autophagy dysfunction, and increased Nrf2 expression, whereas these alterations were abrogated by Nrf2 inhibitor ML385, autophagy inhibitor 3-methyladenine (3-MA, 5 mM) treatment or ATG5 siRNA transfection in HG-induced HK-2 cells. In addition, miR-204-5p inhibitor significantly inhibited miR-204-5p expression and aggravated HG-induced fibronectin and collagen I expression, autophagy dysfunction, and decreased Nrf2 expression, while these alterations were abolished by Nrf2 activator TBHQ. Furthermore, the binding of miR-204-5p with Keap1 was confirmed by luciferase reporter assay and miR-204-5p negatively regulated Keap1 expression, resulting in the activation of Nrf2 pathway. Conclusion MicroRNA-204-5p protects against the progression of diabetic renal fibrosis by restoring autophagy via regulating Keap1/Nrf2 pathway.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-204-5p Ameliorates Renal Injury via Regulating Keap1/Nrf2 Pathway in Diabetic Kidney Disease

Dong,

Liu,

Bian

et al. 2024

DMSO

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“…OTU deubiquitinase 5 (OTUD5), a protein that interacts with GPX4, can promote ferroptosis resistance during ischemia/reperfusion injury by stabilizing GPX4 expression; in turn, hypoxia/ischemia-induced OTUD5 autophagy can destabilize GPX4, leading to ferroptosis-dependent kidney injury ( 96 ). Vitexin has been found to increase GPX4 expression by activating the NRF2/HO-1 pathway, inhibit the ferroptosis of renal tubule epithelial cells, and significantly reduce renal tubule injury, interstitial fibrosis, and renal inflammation in mice with unilateral ureteral obstruction ( 97 ).…”

Section: The Various Forms Of Cell Death and Urolithiasismentioning

confidence: 99%

Cell death‑related molecules and targets in the progression of urolithiasis (Review)

Wu,

Xue,

et al. 2024

Int J Mol Med

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Urolithiasis is a high-incidence disease caused by calcium oxalate (mainly), uric acid, calcium phosphate, struvite, apatite, cystine and other stones. The development of kidney stones is closely related to renal tubule cell damage and crystal adhesion and aggregation. Cell death, comprising the core steps of cell damage, can be classified into various types (i.e., apoptosis, ferroptosis, necroptosis and pyroptosis). Different crystal types, concentrations, morphologies and sizes cause tubular cell damage via the regulation of different forms of cell death. Oxidative stress caused by high oxalate or crystal concentrations is considered to be a precursor to a variety of types of cell death. In addition, complex crosstalk exists among numerous signaling pathways and their key molecules in various types of cell death. Urolithiasis is considered a metabolic disorder, and tricarboxylic acid cycle-related molecules, such as citrate and succinate, are closely related to cell death and the inhibition of stone development. However, a literature review of the associations between kidney stone development, metabolism and various types of cell death is currently lacking, at least to the best of our knowledge. Thus, the present review summarizes the major advances in the understanding of regulated cell death and urolithiasis progression.

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“…Recently, it has been found that repressor element 1-silencing transcription factor (REST) is upregulated in renal tubular epithelial cells of AKI patients and mice and leads to renal injury through the regulation of ferroptosis, and that tubular-specific knockdown of REST significantly attenuates the transition from AKI to CKD and ameliorates renal fibrosis [ 311 ]. Treatment with ferroptosis inducers, such as erastin, decreases GPX 4 activity and enhances intracellular lipid peroxidation to aggravate renal fibrosis [ 312 ]. Pretreatment with ferroptosis inhibitors stopped the progression of renal fibrosis by preventing ferroptosis-related lipid peroxidation and GSH depletion.…”

Section: The Crosstalk Of Abnormal Iron Metabolism and Oxidative Stre...mentioning

confidence: 99%

“…Pretreatment with ferroptosis inhibitors stopped the progression of renal fibrosis by preventing ferroptosis-related lipid peroxidation and GSH depletion. In addition, vitexin attenuates CKD by inhibiting ferroptosis in renal tubular epithelial cells through activation of Nrf2 [ 312 ], and formononetin and tectorigenin attenuate renal fibrosis by inhibiting Smad3 [ 313 , 314 ].…”

Section: The Crosstalk Of Abnormal Iron Metabolism and Oxidative Stre...mentioning

confidence: 99%

Advance in Iron Metabolism, Oxidative Stress and Cellular Dysfunction in Experimental and Human Kidney Diseases

Xie,

Yao,

2024

Antioxidants

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Kidney diseases pose a significant global health issue, frequently resulting in the gradual decline of renal function and eventually leading to end-stage renal failure. Abnormal iron metabolism and oxidative stress-mediated cellular dysfunction facilitates the advancement of kidney diseases. Iron homeostasis is strictly regulated in the body, and disturbance in this regulatory system results in abnormal iron accumulation or deficiency, both of which are associated with the pathogenesis of kidney diseases. Iron overload promotes the production of reactive oxygen species (ROS) through the Fenton reaction, resulting in oxidative damage to cellular molecules and impaired cellular function. Increased oxidative stress can also influence iron metabolism through upregulation of iron regulatory proteins and altering the expression and activity of key iron transport and storage proteins. This creates a harmful cycle in which abnormal iron metabolism and oxidative stress perpetuate each other, ultimately contributing to the advancement of kidney diseases. The crosstalk of iron metabolism and oxidative stress involves multiple signaling pathways, such as hypoxia-inducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. This review delves into the functions and mechanisms of iron metabolism and oxidative stress, along with the intricate relationship between these two factors in the context of kidney diseases. Understanding the underlying mechanisms should help to identify potential therapeutic targets and develop novel and effective therapeutic strategies to combat the burden of kidney diseases.

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Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation

Cited by 13 publications

References 45 publications

MicroRNA-204-5p Ameliorates Renal Injury via Regulating Keap1/Nrf2 Pathway in Diabetic Kidney Disease

MicroRNA-204-5p Ameliorates Renal Injury via Regulating Keap1/Nrf2 Pathway in Diabetic Kidney Disease

Cell death‑related molecules and targets in the progression of urolithiasis (Review)

Advance in Iron Metabolism, Oxidative Stress and Cellular Dysfunction in Experimental and Human Kidney Diseases

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