Targeting the NLRP3 Inflammasome in Diabetic Nephropathy

2021 ◽  
Vol 28 ◽  
Author(s):  
Ming Yang ◽  
Xi Wang ◽  
Yachun Han ◽  
Chenrui Li ◽  
Ling Wei ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
End Stage Renal Disease ◽  
Pathological Process ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Relationship

: Diabetic nephropathy (DN) is one of the most common complications of diabetes and the main cause of end-stage renal disease (ESRD). The inflammatory response plays a key role in the pathological process of DN. As the most deeply studied inflammasome, NLRP3 should not be overlooked in DN. Its abnormal activation accelerates DN progression. In this review, we summarize our understanding of the structural composition and activation factors of the NLRP3 inflammasome. Moreover, the relationship between NLRP3 inflammasome activation, and the potential of the NLRP3 inflammasome as a therapeutic target for DN will also be discussed.

scholarly journals DsbA-L Ameliorates Renal Injury Through the AMPK/NLRP3 Inflammasome Signaling Pathway in Diabetic Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Yang ◽  
Shilu Luo ◽  
Na Jiang ◽  
Xi Wang ◽  
Yachun Han ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Nlrp3 Inflammasome ◽  
Protective Role ◽  
Tubular Damage ◽  
Inflammasome Activation ◽  
Compound C ◽  
Nlrp3 Inflammasome Activation ◽  
Amp Activated Protein Kinase ◽  
Relationship Of ◽  
The Relationship

NLRP3-mediated inflammation is closely related to the pathological progression of diabetic nephropathy (DN). DsbA-L, an antioxidant enzyme, plays a protective role in a variety of diseases by inhibiting ER stress and regulating metabolism. However, the relationship of DsbA-L with inflammation, especially the NLRP3 inflammasome, has not been examined. In this study, we note that activation of the NLRP3 inflammasome and exacerbated fibrosis were observed in the kidneys of diabetic DsbA-L-knockout mice and were accompanied by decreased phosphorylation of AMP-activated protein kinase (AMPK). Moreover, correlation analysis shows that the phosphorylation of AMPK was negatively correlated with NLRP3 expression and tubular damage. In addition, the decreased AMPK phosphorylation and NLRP3 activation induced by high glucose (HG) in HK-2 cells could be alleviated by the overexpression of DsbA-L. Interestingly, the protective effect of DsbA-L was eliminated after treatment with compound C, a well-known AMPK inhibitor. Our findings suggest that DsbA-L inhibits NLRP3 inflammasome activation by promoting the phosphorylation of AMPK.

scholarly journals The Relationship between IL-1β, IL-17, IL-33 and Bcl-2 and the Development of Diabetic Nephropathy

2021 ◽  
Author(s):  
Ahmed Nabil ◽  
Basant Mahmoud ◽  
Adel Abdel-Moneim ◽  
Zinab Negeem
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Cell Lymphoma ◽  
Chronic Renal Disease ◽  
Sodium Concentration ◽  
Positive Correlations ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Relationship

Abstract Background: Diabetic nephropathy (DN) is among the main complications of diabetes mellitus, and it has been the major factor of renal failure. The current investigation aims to address the association between beta-cell lymphoma-2 (Bcl-2), interleukin (IL)-1β, IL-17, and IL-33 with the development of DN. Methods: In this study, twenty healthy volunteers plus hundred patients have been signed up. According to their biochemical markers, patients were categorized into 5 groups; diabetic, chronic renal disease, diabetic chronic renal disease, end-stage renal disease, and diabetic end-stage renal disease. Results: Our results showed a noticeable elevation in IL-1β and IL-17 levels and a reduce in IL-33 and Bcl-2 levels in all investigated groups relative to the healthy group. Positive correlations were reported between IL-1β with FBS and creatinine levels, IL-17, with HbA1c% and sodium levels. However, negative correlations were exerted between IL-33 with urea and sodium concentration, Bcl2 with HbA1c%, and creatinine levels.Conclusion: The present data revealed a marked relationship between Bcl-2, IL-1β, IL-17, and IL-33 levels and the progression of DN. Therefore, understanding the molecular pathways of inflammatory and apoptotic activities-related DN could be translated into the development of therapeutic strategies.

scholarly journals The Profile of Timing Dialysis Initiation in Patients with End-stage Renal Disease in China: A Cohort Study

2020 ◽  
Vol 45 (2) ◽  
pp. 180-193
Author(s):  
Ying Liu ◽  
Luping Wang ◽  
Xianfeng Han ◽  
Yang Wang ◽  
Xuefeng Sun ◽  
...  
Keyword(s):  
Renal Disease ◽  
End Stage Renal Disease ◽  
Cox Regression ◽  
Mainland China ◽  
Dialysis Initiation ◽  
Significant Difference ◽  
Initiation Of Dialysis ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Relationship

Background: Hemodialysis is the main approach for renal replacement therapy in patients with end-stage renal disease (ESRD) in China. The timing of dialysis initiation is one of the key factors influencing patient survival and prognosis. Over the past decade, the relationship between the timing of dialysis initiation and mortality has remained unclear in patients with ESRD in China. Methods: Patients who commenced maintenance hemodialysis from 2009 to 2014 from 24 hemodialysis centers in Mainland China were enrolled in the study (n = 1,674). Patients were divided into 2 groups based on the year they started hemodialysis (patients who started hemodialysis from 2009 to 2011, and patients who started hemodialysis from 2012 to 2014). Analysis of the yearly change in the estimated glomerular filtration rate (eGFR) at the initiation of dialysis was performed for the 2 groups. Meanwhile, the patients were divided into 3 groups based on their eGFR at the initiation of dialysis (<4, 4–8, and >8 mL/min/1.73 m2). For these 3 groups, the relationship between the eGFR at the start of dialysis and mortality were analyzed. Results: The average eGFRs were 5.68 and 5.94 mL/min/1.73 m2 for 2009–2011 and 2012–2014, respectively. Compared with the 2009–2011 group, the proportion of patients with diabetes in 2012–2014 increased from 26.7 to 37.7%. The prognosis of patients with different eGFRs at the start of dialysis was analyzed using Kaplan-Meier survival curves. After adjusting for confounding factors through a Cox regression model, no significant difference was demonstrated among the 3 groups (<4 mL/min/1.73 m2 was used as the reference, in comparison with 4–8 mL/min/1.73 m2 [p = 0.681] and >8 mL/min/1.73 m2 [p = 0.403]). Conclusion: In Mainland China, the eGFR at the start of dialysis did not change significantly over time from 2008 to 2014 and had no association with the mortality of patients with ESRD.

scholarly journals Cichoric Acid Ameliorates Monosodium Urate-Induced Inflammatory Response by Reducing NLRP3 Inflammasome Activation via Inhibition of NF-kB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qi Wang ◽  
Bingfeng Lin ◽  
Zhifeng Li ◽  
Jie Su ◽  
Yulin Feng
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Gouty Arthritis ◽  
Inflammasome Activation ◽  
Cichoric Acid ◽  
Monosodium Urate ◽  
Protein Levels ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α

Gouty arthritis is characterized by the deposition of monosodium urate (MSU) within synovial joints and tissues due to increased urate concentrations. Here, we elucidated the role of the natural compound cichoric acid (CA) on the MSU crystal-stimulated inflammatory response. The THP-1-derived macrophages (THP-Ms) were pretreated with CA and then stimulated with MSU suspensions. The protein levels of p65 and IκBα, the activation of the NF-κB signaling pathway by measuring the expression of its downstream inflammatory cytokines, and the activity of NLRP3 inflammasome were measured by western blotting and ELISA. CA treatment markedly inhibited the degradation of IκBα and the activation of NF-κB signaling pathway and reduced the levels of its downstream inflammatory genes such as IL-1β, TNF-α, COX-2, and PGE2 in the MSU-stimulated THP-M cells. Therefore, we infer that CA effectively alleviated MSU-induced inflammation by suppressing the degradation of IκBα, thereby reducing the activation of the NF-κB signaling pathway and the NLRP3 inflammasome. These results suggest that CA could be a novel therapeutic strategy in averting acute episodes of gout.

scholarly journals Vaspin Alleviates Osteoarthritis by Inhibiting NLRP3-mediated Inflammation

2021 ◽  
Author(s):  
Xianjie Zhu ◽  
Shiyou Dai ◽  
Baohua Xia ◽  
Jianbao Gong ◽  
Bingzheng Ma
Keyword(s):  
Nlrp3 Inflammasome ◽  
Wistar Rat ◽  
Cartilage Degradation ◽  
Pathological Process ◽  
Inflammasome Activation ◽  
Protective Effects ◽  
Collagen Formation ◽  
Nlrp3 Inflammasome Activation

Abstract Background:Osteoarthritis (OA) is a chronic degenerative joint bone disease characterized by cartilage degradation. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is associated with the inflammatory and metabolic responses to OA. However, the underlying mechanisms of the pathological process of OA are not clear. The aim of the present study was to examine the protective effects of vaspin both in vitro and in vivo.Methods:Monosodium iodoacetate (MIA)-induced Wistar rat model of OA was used to assess the in vivo effects of vaspin administered for 12 weeks. The characteristics of OA were evaluated by haematoxylin and eosin (H&E) and safranin O/fast green staining. The anti-inflammatory effect of vaspin was assessed using immunohistochemical, qRT-PCR, and western blotting analysis. Parallel experiments to detect the molecular mechanism through which vaspin prevents OA were performed using LPS-treated chondrocytes.Results:Our results showed that the degeneration of cartilage and upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-13 were ameliorated by vaspin. Additionally, vaspin suppressed the activation of TXNIP/NLRP3 and secretion of tumor necrosis factor ɑ and interleukin-1β in vivo. It was further confirmed that vaspin could also suppress LPS-induced NLRP3 inflammasome activation and reduce collagen formation in chondrocytes. Moreover, vaspin inhibited NLRP3 inflammasome activation by suppressing the ROS/TXNIP pathway.Conclusions: Vaspin inhibited OA by repressing TXNIP/NLRP3 activation in in vitro and in vivo models of OA, thus providing a novel therapeutic strategy for OA.

scholarly journals A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Jie Zheng ◽  
Lu Yao ◽  
Yijing Zhou ◽  
Xiaoqun Gu ◽  
Can Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Atopic Dermatitis ◽  
Epithelial Cells ◽  
Mrna Expression ◽  
Nlrp3 Inflammasome ◽  
Myeloid Cells ◽  
Pathological Process ◽  
Inflammasome Activation ◽  
Mice Model ◽  
Nlrp3 Inflammasome Activation

AbstractAtopic dermatitis (AD) is a common chronic pruritic inflammatory skin disorder characterized by recurrent eczematous lesions. Interleukin (IL)−33, a cytokine of the IL-1 family, was found to play an important role in the pathogenesis of AD. As a key component of the inflammasome, NLRP3 has been mostly described in myeloid cells that to mediate inflammasome activation conducted proinflammatory cytokine production of the IL-1 family. However, the role of NLRP3 inflammasome in the pathogenesis of AD, as well as IL-33 processing are highly controversial. Whether NLRP3 can mediate IL-33 expression and secretion independently of the inflammasome in the epithelium of AD has remained unclear. In this article, we found the mRNA expression of Il33 and Nlrp3 were notably increased in the lesional skin of AD patients compared to healthy controls. We then found a significant positive correlation between the expression of Nlrp3 and Il33 in the epithelium of MC903-mediated AD mice model, but no changes were observed for Il36α, Il36γ, Il1β, or Il18 mRNA expression, as well as IL-1β or IL-18 production. Overexpression of NLRP3 in human immortalized epithelial cells increased IL-33 expression, whereas siRNA targeting NLRP3 abolished IL-33 expression. In addition, inhibition of NLRP3 inflammasome activation or caspase-1 activity with MCC950 or VX-765 showed no effect on the expression and secretion of IL-33 in AD mice. Unlike myeloid cells, NLRP3 predominantly located in the nucleus of epithelial cells, which could directly bind to Il33 specific-promoters and transactivate it through an interaction with transcription factor IRF4. Furthermore, NLRP3 deficient mice exhibited a significant alleviated epidermis inflammation and decreased mRNA expression and secretion of IL-33 in MC903-mediated AD mice without interfering with TSLP and IL-1β production. Our results demonstrate a novel ability of NLRP3 to function as a crucial transcription factor of IL-33 in epithelium independently of inflammasome that to mediate the pathological process of AD.

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