1. Adverse Effects of Simulated Hyper- and Hypo-Phosphatemia on Endothelial Cell Function and Viability
- Author
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Zhihong Liu, Tianfu Wu, Ting Ye, Xin J. Zhou, Caihong Zeng, Jack Hutcheson, Nosratola D. Vaziri, Jiankun Zhu, Chandra Mohan, Ai Peng, and Dinesh Rakheja
- Subjects
Mineral Metabolism and the Kidney ,Anatomy and Physiology ,Hypophosphatemia ,pathways ,Intracellular Space ,phase protein microarrays ,lcsh:Medicine ,cardiovascular-disease ,Apoptosis ,Signal transduction ,030204 cardiovascular system & hematology ,Cardiovascular ,urologic and male genital diseases ,Cardiovascular System ,Biochemistry ,Phosphatidylinositol 3-Kinases ,Hyperphosphatemia ,Molecular cell biology ,0302 clinical medicine ,Akt signaling cascade ,Enos ,Chronic Kidney Disease ,Medicine and Health Sciences ,Endothelial dysfunction ,lcsh:Science ,Cells, Cultured ,Protein Kinase C ,bcl-2-Associated X Protein ,0303 health sciences ,Multidisciplinary ,dysfunction ,Cell Death ,biology ,Chemistry ,NF-kappa B ,apoptosis ,Signaling cascades ,Neurochemistry ,female genital diseases and pregnancy complications ,3. Good health ,Organic Acids ,Nephrology ,Hypertension ,Medicine ,Neurochemicals ,Cellular Types ,flow-cytometry ,Research Article ,musculoskeletal diseases ,medicine.medical_specialty ,MAPK signaling cascades ,Nitric Oxide Synthase Type III ,Cell Survival ,nitric-oxide synthase ,kinase ,Blotting, Western ,Signaling in cellular processes ,bcl-X Protein ,potential consequences ,Nitric Oxide ,Phosphates ,03 medical and health sciences ,Bcl-2-associated X protein ,Vascular Biology ,Internal medicine ,Protein Kinase C beta ,medicine ,Humans ,Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,intracellular calcium ,Mitogen-Activated Protein Kinase Kinases ,Calcium metabolism ,Dose-Response Relationship, Drug ,lcsh:R ,Organic Chemistry ,Endothelial Cells ,nutritional and metabolic diseases ,Protein kinase C signaling ,medicine.disease ,biology.organism_classification ,Endocrinology ,biology.protein ,lcsh:Q ,Calcium ,Phosphonic Acids ,Proto-Oncogene Proteins c-akt ,Neuroscience - Abstract
Author(s): Peng, Ai; Wu, Tianfu; Zeng, Caihong; Rakheja, Dinesh; Zhu, Jiankun; Ye, Ting; Hutcheson, Jack; Vaziri, Nosratola D.; Liu, Zhihong; Mohan, Chandra; Zhou, Xin J. | Abstract: BackgroundDysregulaiton of phosphate homeostasis as occurs in chronic kidney disease is associated with cardiovascular complications. It has been suggested that both hyperphosphatemia and hypophosphatemia can cause cardiovascular disease. The molecular mechanisms by which high or low serum phosphate levels adversely affect cardiovascular function are poorly understood. The purpose of this study was to explore the mechanisms of endothelial dysfunction in the presence of non-physiologic phosphate levels.Methodology/Principal FindingsWe studied the effects of simulated hyper- and hypophosphatemia in human umbilical vein endothelial cells in vitro. We found both simulated hyperphosphatemia and hypophosphatemia decrease eNOS expression and NO production. This was associated with reduced intracellular calcium, increased protein kinase C β2 (PKCβ2), reduced cell viability, and increased apoptosis. While simulated hyperphosphatemia was associated with decreased Akt/p-Akt, Bcl-xl/Bax ratios, NFkB-p65 and p-Erk abundance, simulated hypophosphatemia was associated with increased Akt/p-Akt and Bcl-xl/Bax ratios and p-Mek, p38, and p-p38 abundance.Conclusions/SignificanceThis is the first demonstration of endothelial dysfunction with hypophosphatemia. Our data suggests that both hyperphosphatemia and hypophosphatemia decrease eNOS activity via reduced intracellular calcium and increased PKCβ2. Hyperphosphatemia also appears to reduce eNOS transcription via reduced signaling through PI3K/Akt/NF-kB and MAPK/NF-kB pathways. On the other hand, hypophosphatemia appears to activate these pathways. Our data provides the basis for further studies to elucidate the relationship between altered phosphate homeostasis and cardiovascular disease. As a corollary, our data suggests that the level of phosphate in the culture media, if not in the physiologic range, may inadvertently affect experimental results.
- Published
- 2011