Abstract
Backgroud and PurposeHyperphosphatemia, which is a high inorganic phosphate (Pi) level in the serum, promotes endothelial cells dysfunction and is associated with cardiovascular diseases in patients with chronic kidney diseases (CKD). However, the underlying mechanism of high Pi-induced endothelia cell apoptosis remains unclear.MethodsHuman umbilical vein endothelial cells (HUVECs) were treated with normal Pi (1.0 mM) and high Pi (3.0 mM), and then cell apoptosis, abnormal gene expression and potential signaling pathway involvement in simulated hyperphosphatemia were examined using flow cytometry, quantitative PCR (qPCR) and western blot analysis. A two-step 5/6 nephrectomy was carried out to induce CKD and biochemical measurements were taken.ResultsThe rat model of CKD revealed that hyperphosphatemia is correlated with an increased death-domain associated protein (DAXX) expression in endothelial cells. In vitro, high Pi increased the mRNA and protein expression level of DAXX in HUVECs, effects that were reversed by additional phosphonoformic acid treatment. Functionally, high Pi resulted in a significantly increased apoptosis in HUVECs, whereas DAXX knockdown markedly repressed high Pi-induced cell apoptosis, indicating that DAXX mediated high Pi-induced endothelial cell apoptosis. High Pi treatment and DAXX overexpression induced the activation of extracellular regulated protein kinases (ERKs), while DAXX knockdown inhibited high Pi-induced ERKs activation. Finally, we demonstrated that DAXX overexpression induced HUVECs apoptosis in the presence of normal Pi, whereas additional treatment with U0126 (a specific ERK inhibitor) reversed that effect.ConclusionUpregulated DAXX promoted high Pi-induced HUVECs apoptosis by activating ERK signaling and indicated that the DAXX/ERK signaling axis may be served as a potential target for CKD therapy.
Highlights
Phosphorus, a necessary essential to all living things, is involved in a series of important life processes, including protein synthesis, signal transduction and energy metabolism (Kouloulias, Papaloucas & Papaloucas, 2019)
In the present study we investigated the role of DAXX in the regulating high Pi-induced human umbilical vein endothelial cell (HUVECs) apoptosis and identified its underlying mechanisms
Hyperphosphatemia was correlated with upregulated DAXX expression in endothelial cells Previous studies have identified a number of differentially expressed genes using microarray analysis in high Pi-treated Human umbilical vein endothelial cells (HUVECs) (Qin et al, 2015)
Summary
Phosphorus, a necessary essential to all living things, is involved in a series of important life processes, including protein synthesis, signal transduction and energy metabolism (Kouloulias, Papaloucas & Papaloucas, 2019). DAXX mediates high phosphate-induced endothelial cell apoptosis in vitro through activating ERK signaling. A recent study identified a close correlation between extracellular regulated protein kinase (ERKs)/mitogen-activated protein kinase (MAPK) signaling and endothelial cell apoptosis (Qin et al, 2015). Death domain-associated protein (DAXX), a multifunctional nucleoprotein, plays an important roles in the regulation of cell apoptosis, gene transcription, tumorigenesis and anti-viral infection (Dyer et al, 2017; Li et al, 2013; Li et al, 2017; Tang, Wan & Wu, 2015). In the present study we investigated the role of DAXX in the regulating high Pi-induced human umbilical vein endothelial cell (HUVECs) apoptosis and identified its underlying mechanisms. We concluded that DAXX mediated high Pi-induced endothelial cell apoptosis by activating ERK signaling
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