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Neutrophil extracellular traps promote NLRP3 inflammasome activation and glomerular endothelial dysfunction in diabetic kidney disease

Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therape...

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Main Authors: Gupta, Anubhuti (Author) , Singh, Kunal (Author) , Fatima, Sameen (Author) , Ambreen, Saira (Author) , Zimmermann, Silke (Author) , Younis, Ruaa (Author) , Krishnan, Shruthi (Author) , Rana, Rajiv (Author) , Gadi, Ihsan-Ur-Rehman Khan (Author) , Schwab, Constantin (Author) , Biemann, Ronald (Author) , Shahzad Hussain, Khurrum (Author) , Rani, Vibha (Author) , Ali, Shakir (Author) , Mertens, Peter R. (Author) , Kohli, Shrey (Author) , Isermann, Berend (Author)
Format: Article (Journal)
Language:English
Published: 20 July 2022
In: Nutrients
Year: 2022, Volume: 14, Issue: 14, Pages: 1-15
ISSN:2072-6643
DOI:10.3390/nu14142965
Online Access:Resolving-System, kostenfrei: https://doi.org/10.3390/nu14142965
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2072-6643/14/14/2965
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Author Notes:Anubhuti Gupta, Kunal Singh, Sameen Fatima, Saira Ambreen, Silke Zimmermann, Ruaa Younis, Shruthi Krishnan, Rajiv Rana, Ihsan Gadi, Constantin Schwab, Ronald Biemann, Khurrum Shahzad, Vibha Rani, Shakir Ali, Peter Rene Mertens, Shrey Kohli and Berend Isermann
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Summary:Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose stress in vitro and in vivo. Inhibition of NETs (PAD4 inhibitor) ameliorate endothelial dysfunction and renal injury in DKD. Taken together, NET-induced sterile inflammation promotes diabetes-associated endothelial dysfunction, identifying a new pathomechanism contributing to DKD. Inhibition of NETs may be a promising therapeutic strategy in DKD.
Item Description:Gesehen am 21.11.2022
Physical Description:Online Resource
ISSN:2072-6643
DOI:10.3390/nu14142965

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