Activation of the Lp-PLA2/LPC axis triggers endothelial ferroptosis to drive diabetic kidney disease.

Abstract

Background: Endothelial dysfunction is a key driver of diabetic kidney disease (DKD), but the role of regulated cell death pathways remains unclear. Lipoprotein-associated phospholipase A2 (Lp-PLA2) and its pro-inflammatory product lysophosphatidylcholine (LPC) promote vascular injury; however, their ability to trigger endothelial ferroptosis in DKD is unknown.

Methods: Using a longitudinal db/db mouse model of DKD, we inhibited Lp-PLA2 with Darapladib or administered exogenous LPC. Renal injury, endothelial function, and ferroptosis hallmarks (ROS, ACSL4, GPX4, NOX1) were assessed at multiple timepoints. In vitro, glomerular endothelial cells under high glucose (HG) were treated with Darapladib, LPC, or Lp-PLA2 overexpression to dissect causality..

Results: The Lp-PLA2/LPC axis was progressively activated in DKD mice, correlating with albuminuria, endothelial dysfunction (reduced eNOS, NO, and VEGF; increased ICAM-1 and ADMA), and ferroptotic execution (elevated ROS, ACSL4, and NOX1; decreased GPX4). Darapladib suppressed ferroptosis and attenuated renal injury, whereas LPC exacerbated both. Mechanistically, HG induced ferroptosis in endothelia via Lp-PLA2/LPC activation, which was rescued by Darapladib but amplified by LPC or Lp-PLA2 overexpression.

Conclusion: We identify the Lp-PLA2/LPC axis as a novel activator of endothelial ferroptosis in DKD. Pharmacological blockade with Darapladib protects the kidney by inhibiting this iron-dependent cell death, providing a mechanistically grounded therapeutic strategy independent of glycemic control.