Platelet Cyclophilin D Drives Cholesterol Crystal Embolism-Related Acute Kidney Injury and Kidney Infarction

Cholesterol crystal embolism causes arterial thrombosis, ischemic necrosis, and organ dysfunction. Genetic depletion of cyclophilin D reduced cholesterol crystal embolism-induced thromboinflammation and protected organ function. Pharmacological inhibition of cyclophilin D and transmembrane protein 16F limited cholesterol crystal embolism-induced thrombosis and improved kidney function.

Cholesterol crystal embolism is a severe consequence of advanced atherosclerosis, where intra-arterial cholesterol crystal can trigger organ injury and failure. Cyclophilin D (CypD), a key regulator of the mitochondrial permeability transition pore, promotes procoagulant platelet formation and necrosis. We hypothesized that CypD-dependent procoagulant platelet formation enhances cholesterol crystal embolism-induced thromboinflammatory responses and kidney injury.

We used CypD-deficient mice and pharmacologic inhibitors (cyclosporine A to block CypD and niflumic acid to inhibit transmembrane protein 16F as a downstream effector of CypD) to determine the role of CypD during cholesterol crystal-induced kidney thromboinflammation and injury.

Cholesterol crystal injection into the renal artery caused infarction, thromboinflammation, and AKI in wild-type mice, whereas CypD-deficient mice were protected. Global or platelet-specific CypD deletion preserved GFR, reduced infarct size, and attenuated tubular damage. Pharmacological inhibition of CypD with cyclosporin A conferred similar protection. Inhibition of transmembrane protein 16F-dependent phosphatidylserine exposure with niflumic acid also reduced CypD-mediated procoagulant activity and limited kidney injury.

Our findings identified platelet CypD and downstream phosphatidylserine exposure as key mediators of cholesterol crystal-induced thromboinflammation.