NDT Advance Access originally published online on June 2, 2007
Nephrology Dialysis Transplantation 2007 22(10):2831-2837; doi:10.1093/ndt/gfm269
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Parathyroid hormone stimulates the endothelial nitric oxide synthase through protein kinase A and C pathways
1Laboratory of Renal Physiology, Department of Nephrology and Hypertension, Meir Medical Center, Kfar-Saba and 2Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Correspondence and offprint requests to: Jacques Bernheim, MD, Department of Nephrology and Hypertension, Meir Medical Center, Tchernichovsky 59, Kfar-Saba 44281, Israel. Email: gloriar{at}clalit.org.il
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Abstract |
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Background. Parathyroid hormone (PTH), the major systemic calcium regulating hormone has been implicated in the development of hypertension and the occurrence of uraemic vascular changes. As nitric oxide synthase (NOS) is involved in the production of nitric oxide, and acute PTH effect is characterized by vasodilation, the effect of PTH on the endothelial NOS (eNOS) system was measured in cultured human umbilical cord vein endothelial cells (HUVEC) and the pathways possibly involved were studied.
Methods. The presence of the PTH receptor-1 (PTHR1) on the HUVEC membrane was examined by RT-PCR, immunocytochemistry and western blot. HUVEC were stimulated with 10–12 to 10–10 mol/l PTH. The eNOS mRNA expression was established by RT-PCR and the eNOS protein levels were determined by western blot. The eNOS activity was measured by the conversion of [14C]arginine to [14C]citrulline.
Results. PTHR1 has been found to be expressed in HUVEC and its expression is depressed by increasing concentrations of PTH. PTH induced a significant increase in eNOS mRNA (10–11 mol/l: 1.87 ± 0.16, P = 0.012; 10–10 mol/l: 1.96 ± 0.28, P = 0.007, fold of control), and protein expression. The eNOS activity was also significantly stimulated (10–11 mol/l: 1139 ± 203; 10–10 mol/l: 1323 ± 216 vs control: 621 ± 154 cpm/150 µg protein, P < 0.01). The addition of calphostin C (PKC inhibitor) or Rp-cAMP (PKA inhibitor) reduced the eNOS mRNA, protein expression and activity of PTH-stimulated HUVEC. The combined treatment of calphostin C and Rp-cAMP abolished the eNOS protein expression and activity.
Conclusion. PTH induces an increased activity of the eNOS system; probably both PKA and PKC pathways are involved in this activation. Such data may explain the vasodilation observed after acute treatment with PTH.
Keywords: endothelial cells; nitric oxide synthase; parathyroid hormone; PKA; PKC
Received for publication: 5.10.06
Accepted in revised form: 6. 4.07
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