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Abstract: TH-PO212

Platelets and Neutrophil Extracellular Traps Promote Glomerular Endothelial Dysfunction and Barrier Disruption in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Gupta, Anubhuti, Universitatsklinikum Leipzig, Leipzig, Sachsen, Germany
  • Singh, Kunal, Universitatsklinikum Leipzig, Leipzig, Sachsen, Germany
  • Shahzad, Khurrum, Universitatsklinikum Leipzig, Leipzig, Sachsen, Germany
  • Isermann, Berend Heinrich, Universitatsklinikum Leipzig, Leipzig, Sachsen, Germany
  • Kohli, Shrey, Universitatsklinikum Leipzig, Leipzig, Sachsen, Germany
Background

Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapies to prevent or reverse DKD progression are limited or lacking, respectively. Endothelial dysfunction, platelet-hyperactivity, immune cell infiltration and glomerular filtration barrier (GFB) disruption are associated with DKD. Mechanistic insights concerning the interplay between platelets and neutrophil extracellular traps (NETs) and ensuing endothelial dysfunction for DKD progression limited.

Methods

Renal function, platelet activation and NETs formation was evaluated in a mouse diabetes model. Therapeutic interventions (Aspirin, Anakinra, Solulin, GSK484) were performed after establishment of DKD to study disease reversal. In vitro studies were performed using glomerular endothelial cells (GENC), platelets and neutrophils exposed to high glucose (HG) in static and flow conditions.

Results

Experimental DKD in C57Bl6 mice resulted in albuminuria and increased fractional mesangial area that correlated with activated platelets (CD62P), NETs (H3Cit, NE, PAD4) within glomeruli and plasma NETs markers. In parallel, increased expression of inflammasome markers (NLRP3, IL1β) and reduced expression of thrombomodulin (TM) was observed. In vitro, platelets and NETS exacerbate inflammasome markers (IL1β, NLRP3), reduce endothelial function markers (p-eNOS, KLF2, KLF4 and TM) in GENC and disrupted GFB (enhanced FITC-dextran leakage, disoriented VE cadherin) in HG conditions. Under flow condition, platelets enhanced NETs formation on GENC monolayers exposed to HG. Inhibition of platelet activation (Aspirin), amelioration of NETs (GSK484), targeting P-selectin mediated platelet-neutrophil interactions, IL-1 receptor inhibition (anakinra) or restoring TM expression (solulin) ameliorated these effects in vitro and in vivo. Further experiments evaluating the clinical relevance in diabetic patient cohorts are under progress.

Conclusion

Hyperglycemia promotes platelet-neutrophil interactions resulting in intraglomerular NETs formation, sterile inflammation, glomerular endothelial dysfunction and GFB disruption. This results in aggravated disease course and impaired renal health in DKD. Inhibition of platelets or NETs is a promising therapeutic strategy for DKD.