Abstract Number: PB0771
Meeting: ISTH 2022 Congress
Background: Diabetic kidney disease (DKD) is a major cause of end-stage renal failure and is associated with endothelial dysfunction, platelet-hyperactivity, immune-cell infiltration and dysfunctional glomerular filtration barrier. Mechanistic insights into the role of platelets for DKD progression are limited.
Aims: We aim to scrutinize the mechanistic interplay between platelets and neutrophil extracellular traps (NETs) and ensuing renal thrombo-inflammation in DKD.
Methods: Renal function (albuminuria, fractional mesangial area), platelet activation and NET formation was evaluated in a mouse diabetes model. Therapeutic interventions (Aspirin, Anakinra, Solulin, GSK484) were performed in sub-groups of mice with drugs starting after 16 weeks of diabetes until 24 weeks to study disease reversal. In vitro studies were performed using glomerular endothelial cells (GENCs), platelets and neutrophils exposed to hyperglycaemia under static and flow conditions.
Results: Activated platelets (CD62P) and neutrophil extracellular traps (NETs; CitH3, NE, PAD4) were readily detectable in glomeruli of diabetic mice. Expression of inflammasome markers (NLRP3, IL1β) were positively correlated, reduced thrombomodulin (TM) expression was negatively correlating with NETs. In vitro, platelets exacerbate high glucose and NET induced endothelial dysfunction (p-eNOS, KLF2, KLF4 and TM), sterile inflammation (IL1β, NLRP3), cell death (TUNEL, Caspase-3) and glomerular filtration barrier disruption (enhanced FITC-albumin leakage, disoriented VE cadherin). Under flow conditions, platelets promoted hyperglycaemia induced NET formation on GENCs. Inhibition of platelet activation (Aspirin), amelioration of NETs by inhibition of histone citrullination PAD4 inhibition (GSK484), IL-1 receptor inhibition (anakinra) or restoring TM expression (solulin) ameliorated these effects in vitro and resulted in diabetic kidney disease reversal in vivo.
Conclusion(s): Hyperglycaemia promotes platelet-neutrophil interactions resulting in NETs, hypercoagulability, endothelial sterile inflammation, glomerular endothelial dysfunction, barrier disruption and cell death. These changes aggravate the course of DKD. Inhibition of platelets or NETs is a promising therapeutic strategy for DKD.
To cite this abstract in AMA style:Gupta A, Singh K, Younis R, Krishnan S, Fatima S, Ambreen S, Mai H, Hoffmann N, Biemann R, Shahzad K, Zimmermann S, Isermann B, Kohli S. Platelets promote neutrophil extracellular traps mediated thrombo-inflammation and glomerular endothelial dysfunction in diabetic kidney disease [abstract]. https://abstracts.isth.org/abstract/platelets-promote-neutrophil-extracellular-traps-mediated-thrombo-inflammation-and-glomerular-endothelial-dysfunction-in-diabetic-kidney-disease/. Accessed September 26, 2022.
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