Endoplasmic reticulum stress related factor IRE1α regulates TXNIP/NLRP3-mediated pyroptosis in diabetic nephropathy

Ke, Ruiqiong; Wang, Yan; Hong, Shihua; Lei, Xiao

doi:10.1016/j.yexcr.2020.112293

Cited by 66 publications

(67 citation statements)

References 52 publications

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“…Our TUNEL staining result suggested that pyroptosis mainly occurs in renal tubular epithelial cells. At present, the study of pyrosis focuses on renal tubular epithelial cells, which further supports our outcome (Cheng et al, 2020;Ke, Wang, Hong & Xiao, 2020). Combining with western blotting results suggested that AS-IV could significantly relieve renal cell pyroptosis by reducing the activation of caspase-1, GSDMD, and the secretion of IL-1β and IL-18.…”

Section: Discussionsupporting

confidence: 81%

Astragaloside IV Protects Against Diabetic Nephropathy by Inhibiting Pyroptosis Based on NOX4/TXNIP/NLRP3 Pathway

Zhang¹,

Tao²,

Du³

et al. 2020

Preprint

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Background and Purpose: Diabetic nephropathy (DN) is a common and severe chronic complication in diabetes mellitus. The purpose of this study was to explore the effect and mechanism of Astragaloside IV (AS-IV) on renal pyroptosis in DN. Experimental Approach: High-fat diet and a small dose of streptozotocin were used to establish the DN model. Rats were treated with vehicle or AS-IV (20-, 40- and 80-mg/kg/day) or valsartan (30mg/kg/day) by gavage. After 12 weeks, animals were euthanized; samples of urine and blood were collected to examine biochemical indicators, advanced glycation end products (AGEs), inflammatory cytokines; kidney tissues were collected for histological observation, TUNEL staining, AGEs, inflammatory cytokines, redox indicators, western blot, and immunohistochemistry. Key Results: Biochemical results showed that AS-IV could significantly alleviate the degree of clinical symptoms and the levels of blood glucose, HbA1C, TG, MDA, AGEs, Interleukin (IL)-1β, and IL-18 while improving the activity of SOD and the secretion and sensitivity of insulin. Histological examination and TUNEL staining indicated that AS-IV attenuated the damage of tissues and cells in the kidney from DN rats. Western blot results revealed that AS-IV relieved the activation of NOX4/TXNIP/NLRP3 pathway and the expression of collagen IV and fibronectin in DN rats. Immunohistochemistry results showed that AS-IV attenuated collagen IV and fibronectin in the kidney from DN rats. Conclusion and Implications: The NOX4/TXNIP/NLRP3 pathway mediated renal pyroptosis could play a crucial role in kidney damage and DN development in rats. Restoration of renal pyroptosis by AS-IV be a potential therapeutic strategy against DN.

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Section: Discussionsupporting

confidence: 81%

Astragaloside IV Protects Against Diabetic Nephropathy by Inhibiting Pyroptosis Based on NOX4/TXNIP/NLRP3 Pathway

Zhang¹,

Tao²,

Du³

et al. 2020

Preprint

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“…Pyroptosis is another type of programmed cell death associated with inflammatory caspase 1 and proinflammatory regulators that are common in necrosis and apoptosis [27], and is closely linked to the activation of the inflammatory pathway. As observed in ERS involving the TXNIP/NLRP3 cascade with elevation in the degradation of miR-200a induced pyroptosis and leads to renal failure in a mouse model [31].…”

Section: Signaling Pathways Involving Thioredoxin-interacting Proteinmentioning

confidence: 79%

“…Another mechanism induces TXNIP by endoplasmic-reticulum stress (ERS; once the capacity of the ER to fold proteins reaches a saturated level); misfolded proteins induce the cell to consume reduced TXN to obtain energy in the form of NADPH for modifying these proteins (for correction), thereby causing cellular stress that triggers an inflammatory response. The upregulation of TXNIP by ERS is mediated by inositol-requiring enzyme 1a (IRE1a) and protein kinase R-like endoplasmic reticulum kinase (PERK) in β-cells [31]. IRE1a overexpression activates TXNIP via reducing activity of microRNA-17 (miR-17), which is a TXNIP-destabilizing microRNA.…”

Section: Signaling Pathways Involving Thioredoxin-interacting Proteinmentioning

confidence: 99%

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

Qayyum

Haseeb

Kim

et al. 2021

IJMS

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Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.

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“…Therefore, the inhibition of inflammasome/TXNIP may be a potential treatment for DN. Ke et al (2020) found that in DN rats, the levels of NLRP3 inflammasome, TXNIP, the pyroptosis-related protein were increased, while silencing TXNIP by lentivirus vector reversed the changes, suggesting that the inhibition of TXNIP/NLRP3 improved renal injury through inhibiting pyroptosis in DN rats. Evidence indicated that ERS regulate pyroptosis through TXNIP/NLRP3 Dong et al, 2020).…”

Section: The Role Of the Effects Of Ers On Nlrp3 Inflammasome In Diabetic Nephropathymentioning

confidence: 93%

“…The similar results were obtained in HG-induced NRK-52E cell. In sum, the inhibition of IRE1α-mediated ERS can improve DN by downregulating TXNIP/NLRP3 inflammasome-mediated pyroptosis (Ke et al, 2020). In addition to IRE1α, PERK is also an ERS-related protein.…”

Section: The Role Of the Effects Of Ers On Nlrp3 Inflammasome In Diabetic Nephropathymentioning

confidence: 99%

The Role of the Effects of Endoplasmic Reticulum Stress on NLRP3 Inflammasome in Diabetes

Wang

2021

Front. Cell Dev. Biol.

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Endoplasmic reticulum (ER) is an important organelle for the protein synthesis, modification, folding, assembly, and the transport of new peptide chains. When the folding ability of ER proteins is impaired, the accumulation of unfolded or misfolded proteins in ER leads to endoplasmic reticulum stress (ERS). The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, can induce the maturation and secretion of interleukin-1beta (IL-1β) and IL-18 through activating caspase-1. It is associated with many diseases. Studies have shown that ERS can regulate NLRP3 inflammasome in many diseases including diabetes. However, the mechanism of the effects of ERS on NLRP3 inflammasome in diabetes has not been fully understood. This review summarizes the recent researches about the effects of ERS on NLRP3 inflammasome and the related mechanism in diabetes to provide ideas for the relevant basic research in the future.

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Endoplasmic reticulum stress related factor IRE1α regulates TXNIP/NLRP3-mediated pyroptosis in diabetic nephropathy

Cited by 66 publications

References 52 publications

Astragaloside IV Protects Against Diabetic Nephropathy by Inhibiting Pyroptosis Based on NOX4/TXNIP/NLRP3 Pathway

Astragaloside IV Protects Against Diabetic Nephropathy by Inhibiting Pyroptosis Based on NOX4/TXNIP/NLRP3 Pathway

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

The Role of the Effects of Endoplasmic Reticulum Stress on NLRP3 Inflammasome in Diabetes

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