Abstract
BackgroundChronic kidney disease (CKD) has been considered as a major health problem in the world. Increasing uric acid (UA) could induce vascular endothelial injury, which is closely related to microinflammation, oxidative stress, and disorders of lipids metabolism. However, the specific mechanism that UA induces vascular endothelial cells injury in early CKD remains unknown.MethodsHuman umbilical vein endothelial cells (HUVECs) were cultured and subjected to different concentrations of UA for different periods. Early CKD rat model with elevated serum UA was established. Western blotting and quantitative real-time PCR (qPCR) were applied for measuring protein and mRNA expression of different cytokines. The animals were sacrificed and blood samples were collected for measurement of creatinine, UA, IL-1β, TNF-α, and ICAM-1. Renal tissues were pathologically examined by periodic acid-Schiff (PAS) or hematoxylin-eosin (HE) staining.ResultsThe expression of IL-1β, ICAM-1, NLRP3 complexes, and activation of NLRP3 inflammasome could be induced by UA, but the changes induced by UA were partially reversed by siRNA NLRP3 or caspase 1 inhibitor. Furthermore, we identified that UA regulated the activation of NLRP3 inflammasome by activating ROS and K+ efflux. In vivo results showed that UA caused the vascular endothelial injury by activating NLRP3/IL-1β pathway. While allopurinol could reduce UA level and may have protective effects on cardiovascular system.ConclusionsUA could regulate NLRP3/IL-1β signaling pathway through ROS activation and K+ efflux and further induce vascular endothelial cells injury in early stages of CKD.
Highlights
Chronic kidney disease (CKD) has been considered as a major health problem in the world
uric acid (UA) induced the expression of Interleukin-1 beta (IL-1β) and intercellular adhesion molecule1 (ICAM-1) in Human umbilical vein endothelial cells (HUVECs) After treatment with different concentrations of UA or different incubation time, the expression of ICAM-1 and IL-1β in HUVECs was detected by western blotting and quantitative real-time PCR (qPCR) (Fig. 1)
UA induced the expression of NLRP3 complexes and activation of NLRP3 inflammasome in HUVECs In order to investigate the effects of UA on NLRP3 inflammasome, the expression of NLRP3, associated speck-like protein (ASC), and procaspase 1 was measured by western blotting and qPCR after the treatment by different concentrations or different incubation time of UA (Fig. 2)
Summary
Chronic kidney disease (CKD) has been considered as a major health problem in the world. Increasing uric acid (UA) could induce vascular endothelial injury, which is closely related to microinflammation, oxidative stress, and disorders of lipids metabolism. The specific mechanism that UA induces vascular endothelial cells injury in early CKD remains unknown. Activation of NLRP3 inflammasome in vascular endothelial cells eventually leads to endothelial dysfunction and contributes to the development of cardiovascular diseases [13]. NLRP3/IL-1β pathway may be closely related to vascular endothelial cells injury. In early-stage CKD patients whether UA activates NLRP3/IL-1β and further induces vascular endothelial cells injury through ROS activation and K+ efflux are still not well known
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