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Routine Screening Method for Microparticles in Platelet Transfusions
Published on: January 31, 2018
Platelet Microparticles Mediate Glomerular Endothelial Injury in Early Diabetic Nephropathy
Yang Zhang1, Kun Ling Ma2, Yu Xiang Gong1
1Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; and.
Background:
Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction.
Methods:
We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry.
Results:
Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury.
Conclusions:
These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.
Insights
Platelet microparticles worsen glomerular endothelial injury in early diabetic nephropathy by activating the mTORC1 pathway and via CXCL7. Targeting CXCL7 may offer a therapeutic strategy for diabetic kidney disease.
Area of Science:
- Vascular Biology
- Diabetology
- Nephrology
Background:
- Glomerular endothelium dysfunction is key in early diabetic nephropathy pathogenesis, potentially driven by metabolic issues.
- Platelet microparticles (extracellular vesicles from activated platelets) are emerging regulators of vascular dysfunction.
Purpose of the Study:
- To investigate the impact of platelet microparticles on glomerular endothelial injury in a rat model of early diabetic nephropathy.
- To explore the underlying mechanisms, including the mTORC1 pathway and CXCL7, involved in microparticle-induced injury.
Main Methods:
- Streptozotocin-induced diabetic rats and primary rat glomerular endothelial cells were used.
- Platelet microparticle levels were quantified using flow cytometry.
- Mechanisms investigated included reactive oxygen species production, nitric oxide levels, endothelial nitric oxide synthase and SOD activity, and pathway activation (mTORC1).
Main Results:
- Diabetic rats showed increased plasma platelet microparticles, reduced by aspirin.
- In vitro, platelet microparticles induced oxidative stress, reduced nitric oxide, and increased endothelial barrier permeability.
- Platelet microparticles activated the mTORC1 pathway and utilized CXCL7 to mediate glomerular endothelial injury, both inhibited by specific blockers.
Conclusions:
- Platelet microparticles play a pathogenic role in glomerular endothelium dysfunction in early diabetic nephropathy.
- The mTORC1 pathway and CXCL7 are critical mediators of this injury.
- CXCL7 presents a potential therapeutic target for treating early diabetic nephropathy.
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