2. Academic Validation
  3. High phosphate impairs arterial endothelial function through AMPK-related pathways in mouse resistance arteries

High phosphate impairs arterial endothelial function through AMPK-related pathways in mouse resistance arteries

  • Acta Physiol (Oxf). 2021 Apr;231(4):e13595. doi: 10.1111/apha.13595.
Weipeng Hu 1,  Shan Jiang 1,  Yixin Liao 2,  Jinhong Li 3,  Fang Dong 1,  Jie Guo 1,  Xiaohua Wang 3,  Lingyan Fei 3,  Yu Cui 1,  Xiaoqiu Ren 1,  Nan Xu 1,  Liang Zhao 1 4,  Limeng Chen 5,  Yali Zheng 6,  Lingli Li 7,  Andreas Patzak 8,  Pontus B Persson 8,  Zhihua Zheng 3,  En Yin Lai 1 3 4 8
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Department of Nephrology, Center of Kidney, The Seventh Affiliate Hospital, Sun Yat-sen University, Shenzhen, China.
  • 4 Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
  • 5 Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
  • 6 Department of Nephrology, Ningxia people's hospital, Yinchuan, China.
  • 7 Division of Nephrology and Hypertension, Georgetown University, Washington, DC, USA.
  • 8 Institute of Vegetative Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
PMID: 33835704 DOI: 10.1111/apha.13595
Abstract

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.

Keywords

AMPK; afferent arteriole; endothelial dysfunction; nitric oxide; phosphate.

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