Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy

Qian, Cheng; Pan, Jing; Zhou, Zhuanli; Yin, Fang‐Fang; Xie, Hongyan; Chen, Pan‐Pan; Li, Jingyao; Zheng, Pinpin; Zhou, Li; Zhang, Wei; Li, Jun; Lü, Limin

doi:10.1038/s41401-020-00525-z

Cited by 118 publications

(97 citation statements)

References 29 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: 77%

“…The occurrence and development of DN are closely related to many factors (Kandhare, Mukherjee & Bodhankar, 2017;Zheng, Powell, Zheng, Kantharidis & Gnudi, 2016), including inflammation. With the release of pro-inflammatory factors, pyroptosis is a new pro-inflammatory programmed death process and is closely related to DN development (Cheng et al, 2020). Astragaloside IV (AS-IV) is the principal active substance of Astragalus membranaceus (Fisch) Bge (Astragalus), which was identified that AS-IV had potent antidiabetes, anti-inflammation, anti-oxidation, antifibrosis (Li, Hou, Xu, Liu & Tu, 2017).…”

Section: Introductionmentioning

confidence: 99%

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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: 77%

Section: Introductionmentioning

confidence: 99%

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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“…Our previous study demonstrated UII expression had a positive correlation with ER stress markers GRP78 and CHOP, blood pressure (21). Elevated Ca 2+ concentration could induce activation of NLRP3, UII could increase intracellular calcium concentration (26), and Cheng et al (25) also reported that ER induced pyroptosis initiator NLRP3 upregulation. In view of these, we speculated that UII might have correlation with pyroptosis markers upregulation of placenta.…”

Section: Discussionmentioning

confidence: 93%

“…We also firstly found that pyroptosis-related molecules such as caspase-1 and GSDMD were positively correlated with urine protein excretion in patients with severe preeclampsia. Cheng et al (25) reported that the expression pyroptosis markers caspase-11, GSDMD, and cleaved N-gasdermin D (GSDMD-N) in podocytes were significantly increased, accompanied by decreased expression of podocyte markers nephrin and podocin, loss and fusion in podocyte foot processes, increased inflammatory cytokines NF-κB, IL-1β, and IL-18, macrophage infiltration, glomerular matrix expansion and increased urinary albumin. All these changes in diabetic mice were attenuated by knockout of caspase-11 or GSDMD.…”

Section: Discussionmentioning

confidence: 99%

Expression of urotensin II is positively correlated with pyroptosis-related molecules in patients with severe preeclampsia

Pan

Zhang

et al. 2020

Clinical and Experimental Hypertension

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“…C4BPA [209], KYNU (kynureninase) [210], ORM1 [211], ARSA (arylsulfatase A) [212], CYB5R3 [213], MAT1A [214], SDC4 [215], ASL (argininosuccinate lyase) [216], SLC4A4 [217], EPHB6 [218], SPARCL1 [219], THBS2 [220], EFNB2 [221] and CD248 [222] were revealed to be associated with hypertension, but these genes might be involved in progression of T2DM. GSDMD (gasdermin D) [223], UNC5B [224] and PDGFB (platelet derived growth factor subunit B) [225] have been reported significantly expressed in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

Vastrad¹,

Vastrad²

2021

Preprint

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Type 2 diabetes mellitus (T2DM) is etiologically related to metabolic disorder. The aim of our study was to screen out candidate genes of T2DM and to elucidate the underlying molecular mechanisms by bioinformatics methods. Expression profiling by high throughput sequencing data of GSE154126 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between T2DM and normal control were identified. And then, functional enrichment analyses of gene ontology (GO) and REACTOME pathway analysis was performed. Protein protein interaction (PPI) network and module analyses were performed based on the DEGs. Additionally, potential miRNAs of hub genes were predicted by miRNet database. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst database. Further, validations were performed by receiver operating characteristic curve (ROC) analysis and real time polymerase chain reaction (RT PCR). In total, 925 DEGs were identified in T2DM, including 447 up regulated genes and 478 down-regulated genes. Functional enrichment analysis results showed that up regulated DEGs were significantly enriched in defense response, neutrophil degranulation, cell adhesion and extracellular matrix organization. The top 10 hub genes, JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 were identified from the PPI network, modules, miRNA hub gene regulatory network and TF hub gene regulatory network. Furthermore, ROC analysis and RT PCR revealed that JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 might serve as biomarkers in T2DM. Bioinformatics analysis is a useful tool to explore the molecular mechanism and pathogenesis of T2DM. The identified hub genes may participate in the onset and advancement of T2DM and serve as therapeutic targets.

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Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy

Cited by 118 publications

References 29 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

Expression of urotensin II is positively correlated with pyroptosis-related molecules in patients with severe preeclampsia

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

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