Uric acid regulates NLRP3/IL-1β signaling pathway and further induces vascular endothelial cells injury in early CKD through ROS activation and K+ efflux

Abstract

Background 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. However, the specific mechanism that UA induces vascular endothelial cells injury in early CKD remains unknown. Methods Human 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. Results The 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. Conclusions UA 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.

High Concentrations of Uric Acid and Angiotensin II Act Additively to Produce Endothelial Injury

“…Therefore, we believe that Ang II and HUA act additively to cause endothelial cell injury. Besides those, we also found uric acid and Ang II not only induced IL-1beta and IL-18 secretion of endothelial cell individually, similarly with other reports [31,32], but also UA can aggravate those inflammatory mediator secretions that are induced by Ang II. The mechanism maybe uric acid and Ang II triggers the activation of inflammasome such as NLRP3 [32,33].…”

Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective

“…Studies by Wang et al report that UA can activate nod-like receptor protein 3 (NLRP3) inflammasomes and damage mitochondria, resulting in cellular damage of H9c2 cells ( Wang et al, 2018 ). In addition, several studies also show that UA activates the NLRP3 inflammasome and induces interleukin-1β (IL-1β) release in a variety of cells, including monocytes, macrophages, vascular smooth muscle cells, and endothelial cells ( Martinon et al, 2006 ; Matias et al, 2015 ; Alberts et al, 2019 ; Kim et al, 2019 ; Li et al, 2019 ; Yin et al, 2019 ). The molecular mechanism of UA-induced NLRP3/IL-1 β activation is through NF-κB activation and mitochondrial ROS (mROS) ( Figure 2 ).…”

The Efficacy and Mechanism of Chinese Herbal Medicines in Lowering Serum Uric Acid Levels: A Systematic Review

“…In addition to the inflammatory process, oxidative stress is one of the early events related to the elevated sUA. Uric acid entering cells can rapidly induce oxidative stress ( Ko et al, 2019 ; Yin et al, 2019 ). This state of oxidative stress is governed by the balance between ROS production and their elimination by antioxidants.…”