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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:87855 |
| Date | 02 November 2023 |
| Creators | Gupta, Anubhuti, Singh, Kunal, Fatima, Sameen, Ambreen, Saira, Zimmermann, Silke, Younis, Ruaa, Krishnan, Shruthi, Rana, Rajiv, Gadi, Ihsan, Schwab, Constantin, Biemann, Ronald, Shahzad, Khurrum, Rani, Vibha, Ali, Shakir, Mertens, Peter Rene, Kohli, Shrey, Isermann, Berend |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2965 |
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