NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy

Hou, Yun; Lin, Shiji; Qiu, Jun; Sun, Wangnan; Ma, Dong; Xiang, Yuzhi; Wang, Lin; Du, Pengchao

doi:10.1016/j.bbrc.2019.10.194

Cited by 54 publications

(45 citation statements)

References 31 publications

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“…Podocyte dysfunction is prominent during proteinuria progression in several glomerular diseases [1]. Accumulating evidence suggests that microinflammation, a chronic lowgrade inflammatory state that is involved in the pathological process of diabetic nephropathy (DN), leads to podocyte dysfunction [1][2][3]. When subjected to harmful stimuli, such as continuous chronic hyperglycemia, multiple metabolic pathways are disrupted.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Wang

Gao

et al. 2021

Journal of Diabetes Research

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Objective. Microinflammation plays a crucial role in podocyte dysfunction in diabetic nephropathy, but its regulatory mechanism is still unclear. This study is aimed at discussing the mechanisms underlying the effect of miRNA-155 on podocyte injury to determine its potential as a therapeutic target. Methods. Cultured immortalized mouse podocytes and diabetic KK-Ay mice models were treated with a miR-155 inhibitor. Western blotting, real-time PCR, ELISA, immunofluorescence, and Luciferase reporter assay were used to analyze markers of inflammation cytokines and podocyte injury. Results. miRNA-155 was found to be highly expressed in serum and kidney tissue of mice with diabetic nephropathy and in cultured podocytes, accompanied by elevated levels of inflammatory factors. Inhibition of miRNA-155 can reduce proteinuria and ACR levels, diminish the secretion of inflammatory molecules, improve kidney function, inhibit podocyte foot fusion, and reverse renal pathological changes in diabetic nephropathy mice. Overexpression of miRNA-155 in vitro can increase inflammatory molecule production in podocytes and aggravates podocyte injury, while miRNA-155 inhibition suppresses inflammatory molecule production in podocytes and reduces podocyte injury. A luciferase assay confirmed that miRNA-155 could selectively bind to 3 ′ -UTR of SIRT1, resulting in decreased SIRT1 expression. In addition, SIRT1 siRNA could offset SIRT1 upregulation and enhance inflammatory factor secretion in podocytes, induced by the miRNA-155 inhibitor. Conclusions. These findings strongly support the hypothesis that miRNA-155 inhibits podocyte inflammation and reduces podocyte injury through SIRT1 silencing. miRNA-155 suppression therapy may be useful for the management of diabetic nephropathy.

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Section: Introductionmentioning

confidence: 99%

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Wang

Gao

et al. 2021

Journal of Diabetes Research

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“…NLRP3 was also reported to be involved in kidney injury, including renal I/R injury. It was demonstrated that NLRP3/E3 ubiquitin-protein ligase XIAP signaling aggravated renal fibrotic injury, and also NLRP3 inflammasome activation negatively regulated podocyte autophagy in diabetic nephropathy ( 10 , 11 ). Additionally, a humanized IL-6 receptor (IL-6R) antibody could reduce the activation of NLRP3 inflammasome in diabetic nephropathy, partly via suppressing IL-17A, which could be suppressed by neutralization of IL-17C in renal I/R ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

Tetramethylpyrazine alleviates acute kidney injury by inhibiting NLRP3/HIF‑1α and apoptosis

Sun

Wang

et al. 2020

Mol Med Rep

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The aim of the present study was to investigate the protective effect and underlying mechanism of tetramethylpyrazine (TMP) on renal ischemia reperfusion injury (RIRI) in rats, which refers to the injury caused by the restoration of blood supply and reperfusion of the kidney after a period of ischemia. Sprague-Dawley rats were randomly divided into a Sham group, renal ischemia-reperfusion (I/R) group and TMP group. TMP hydrochloride (40 mg/kg, 6 h intervals) was given via intraperitoneal injection immediately after reperfusion in the TMP group, after 24 h the kidney tissues were taken for follow-up experiments. Pathological changes in the kidney tissues were observed by periodic acid-Schiff staining. Renal function was assessed by measuring levels of serum creatinine and blood urea nitrogen, and inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. Renal cell apoptosis was detected by TUNEL-DAPI double staining, mRNA and protein changes were analyzed by reverse transcription-quantitative PCR and western blotting. Cell viability was measured using a CCK-8 assay. It was found that the renal tissues of the sham operation group were notably abnormal, and the renal tissues of the I/R group were damaged, while the renal tissues of the TMP group were less damaged compared with those of the I/R group. Compared with the I/R group, the serum creatinine and blood urea nitrogen levels in the TMP group were low (all P<0.05), levels of inflammatory cytokines TNF-α and IL-6 decreased, the apoptotic rate was low (all P<0.05), and the relative expression levels of nucleotide-oligomerization domain-like receptor 3 (NLRP3) protein and mRNA in renal tissues were low (all P<0.05). The expression levels of hypoxia-inducible factor 1-α and NLRP3 increased after oxygen and glucose deprivation (OGD), and reduced after treatment with OGD and TMP (all P<0.05). It was concluded that TMP can reduce renal injury and improve renal function in RIRI rats, and its mechanism may be related to the reduction of NLRP3 expression in renal tissues.

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“…Interestingly, the level of NLRP3 mRNA is also notably positively correlated with the urinary albumin/creatinine ratio, serum creatinine (El-Horany et al, 2017). Similarly, activation of the NLRP3 inflammasome is also observed in mice with STZ-induced DN (Hou et al, 2020) or in db/db mice (Yi et al, 2017), and inhibition of NLRP3 inflammasome activation by chemical treatment or gene knockout alleviated renal inflammation and pathological progression in mice with DN (Ding et al, 2018;Wu et al, 2018). These results suggest that NLRP3 inflammasome activation plays an indispensable role in the pathogenesis of DN.…”

Section: Introductionmentioning

confidence: 83%

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

et al. 2021

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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.

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NLRP3 inflammasome negatively regulates podocyte autophagy in diabetic nephropathy

Cited by 54 publications

References 31 publications

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Tetramethylpyrazine alleviates acute kidney injury by inhibiting NLRP3/HIF‑1α and apoptosis

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

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