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High phosphate impairs arterial endothelial function through AMPK‐related pathways in mouse resistance arteries
Author(s) -
Hu Weipeng,
Jiang Shan,
Liao Yixin,
Li Jinhong,
Dong Fang,
Guo Jie,
Wang Xiaohua,
Fei Lingyan,
Cui Yu,
Ren Xiaoqiu,
Xu Nan,
Zhao Liang,
Chen Limeng,
Zheng Yali,
Li Lingli,
Patzak Andreas,
Persson Pontus B.,
Zheng Zhihua,
Lai En Yin
Publication year - 2021
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13595
Subject(s) - mesenteric arteries , endocrinology , medicine , vasodilation , enos , endothelial dysfunction , endothelium , ampk , oxidative stress , reactive oxygen species , biology , chemistry , nitric oxide , nitric oxide synthase , microbiology and biotechnology , phosphorylation , artery , protein kinase a
Aims In patients with renal disease, high serum phosphate shows a relationship with cardiovascular risk. We speculate that high phosphate (HP) impairs arterial vasodilation via the endothelium and explore potential underlying mechanisms. Methods Isolated vessel relaxation, endothelial function, glomerular filtration rate (GFR), oxidative stress status and protein expression were assessed in HP diet mice. Mitochondrial function and protein expression were assessed in HP‐treated human umbilical vein endothelial cells (HUVECs). Results High phosphate (1.3%) diet for 12 weeks impaired endothelium‐dependent relaxation in mesenteric arteries, kidney interlobar arteries and afferent arterioles; reduced GFR and the blood pressure responses to acute administration of acetylcholine. The PPARα/LKB1/AMPK/eNOS pathway was attenuated in the endothelium of mesenteric arteries from HP diet mice. The observed vasodilatory impairment of mesenteric arteries was ameliorated by PPARα agonist WY‐14643. The phosphate transporter PiT‐1 knockdown prevented HP‐mediated suppression of eNOS activity by impeding phosphorus influx in HUVECs. Endothelium cytoplasmic and mitochondrial reactive oxygen species (ROS) were increased in HP diet mice. Moreover HP decreased the expression of mitochondrial‐related antioxidant genes. Finally, mitochondrial membrane potential and PGC‐1α expression were reduced by HP treatment in HUVECs, which was partly restored by AMPKα agonist. Conclusions HP impairs endothelial function by reducing NO bioavailability via decreasing eNOS activity and increasing mitochondrial ROS, in which the AMPK‐related signalling pathways may play a key role.