The Role of Platelets in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is among the most common microvascular complications in patients with diabetes, and it currently accounts for the majority of end-stage kidney disease cases worldwide. The pathogenesis of DKD is complex and multifactorial, including systemic and intra-renal inflammatory and coagulation processes. Activated platelets play a pivotal role in inflammation, coagulation, and fibrosis. Mounting evidence shows that platelets play a role in the pathogenesis and progression of DKD. The potentially beneficial effects of antiplatelet agents in preventing progression of DKD has been studied in animal models and clinical trials. This review summarizes the current knowledge on the role of platelets in DKD, including the potential therapeutic effects of antiplatelet therapies.

Keywords: antiplatelet; biomarker; diabetes; diabetic kidney disease; diabetic nephropathy; platelet activation; platelets.

Figure 1

Mechanisms of platelet involvement in the pathogenesis of diabetic kidney disease. Under diabetic conditions, platelet hyperreactivity is characterized by increased activation and signaling of platelet receptors, leading to platelet adhesion, activating other platelets to form aggregates, and contributing to the coagulation cascade. Activated platelets directly bind to leukocytes through a P-selectin–PSGL-1, CD40-CD40L interaction and stimulate leukocytes extravasation. Soluble CD40L produced by activated platelet binds to αIIbβ3 and α5β1 integrin and mediates platelet activation. sCD40L may affect podocytes, leading to an increase in the expression of MMP9 and enhancing glomerular permeability. PAR receptors are also expressed in platelets, which can be activated by thrombin signaling, thus mediating platelet activation. Platelet activation releases cytokines and chemokines such as RANTES/CCL5, PF4/CXCL4, and β-TG/CXCL7. Platelets contain numerous growth factors such as PDGF, which contribute to mesangial cell proliferation and matrix accumulation in DKD. With TSP-1, PDGF also stimulates and activates the release of TGF-β, responsible for mesangial matrix accumulation, renal infiltration with inflammatory cells, and podocyte damage. TXA2 and PAF secrete from platelets, increase platelet aggregation, and enhance glomerular permeability, inducing proteinuria. PAF also play a part in subsequent inflammatory reaction and stimulate ECM deposition. Platelets also release abundant MVs and induce the production of ROS, decrease NO, and inhibit the activities of eNOS and SOD. Platelet MVs also contribute to the injury of glomerular endothelial cells by releasing CXCL7.