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

Abstract

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 (MPTP), 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 TMEM16F as a downstream effectorof 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 acute kidney injury (AKI) in wild-type mice, whereas CypD-deficient mice were protected. Global or platelet-specific CypD deletion preserved glomerular filtration rate, reduced infarct size, and attenuated tubular damage. Pharmacological inhibition of CypD with cyclosporin A conferred similar protection. Inhibition of TMEM16F-dependent phosphatidylserine (PS) exposure with niflumic acid also reduced CypD-mediated procoagulant activity and limited kidney injury. Our findings identified platelet CypD and downstream PS exposure as key mediators of cholesterol crystal-induced thromboinflammation.