Abstract
Vascular calcification is a complication of diseases and conditions such as chronic kidney disease, diabetes, and aging. Previous studies have demonstrated that high concentrations of inorganic phosphate (Pi) can induce oxidative stress and vascular smooth muscle cell calcification. KEAP1 (Kelch-like ECH-associated protein 1)/NF-E2-related factor 2 (NRF2) signaling has been shown to play important roles in protecting cells from oxidative stress. The current study aims to investigate the possible involvement of the KEAP1/NRF2/P62 -mediated antioxidant pathway in vascular calcification induced by high Pi levels. Exposure of vascular smooth muscle cells (VSMCs) to high Pi concentrations promoted the accumulation of reactive oxygen species (ROS) and the nuclear translocation of NRF2, along with an increase in P62 levels and a decrease in KEAP1 levels. A classic NRF2 activator, tert-butylhydroquinone (tBHQ), significantly decreased ROS levels and calcium deposition in VSMCs by promoting the nuclear translocation of NRF2 and upregulating P62 and KEAP1 expression. In contrast, silencing NRF2 and P62 with siRNAs increased the levels of ROS and calcium deposition in VSMCs. In conclusion, VSMC calcification can be alleviated by the activation of the KEAP1/NRF2/P62 antioxidative pathway, which could have a protective role when it is exogenously activated by tBHQ.
Highlights
Arterial calcification is a common complication of chronic kidney disease (CKD), atherosclerosis, diabetes, and chronic heart failure[1,2,3,4]
vascular smooth muscle cells (VSMCs) exposed to high Pi medium exhibited a 4.3-fold increase in fluorescence intensity compared with that of control cells (Figure 1A)
These results indicate that crosstalk exists between KEAP1, NRF2, and P62 when VSMCs are exposed to high Pi concentration
Summary
Arterial calcification is a common complication of chronic kidney disease (CKD), atherosclerosis, diabetes, and chronic heart failure[1,2,3,4]. It has already been found that vascular calcification is an active cell-mediated process that occurs in response to abnormal environmental cues, including oxidative stress, inflammatory cytokines, alterations in the extracellular matrix and increased calcium and phosphate levels, similar to bone development[3,7,8,9]. During this process, the differentiated vascular smooth muscle cells (VSMCs) undergo dedifferentiation and subsequently undergo osteogenic transition, which results in vascular calcification[10]. We aimed to determine the possible involvement of the KEAP1/NRF2/P62 antioxidant pathway in VMSC calcification induced by high Pi levels
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