Housekeeping gene expression in myogenic cell cultures from neurodegeneration and denervation animal models |
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Authors: | Manzano Raquel Toivonen Janne M Calvo Ana C Muñoz Maria Jesús Zaragoza Pilar Osta Rosario |
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Affiliation: | aDivision of Nephrology, University of California, San Francisco, USA;bDivision of Cardiology, University of California, San Francisco, USA;cCardiovascular Research Institute, University of California, San Francisco, USA;dEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, USA |
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Abstract: | Uremic toxins such as indoxyl sulfate (IS) accumulate at a high level in end stage renal disease (ESRD) and can exhibit significant systemic endothelial toxicity leading to accelerated cardiovascular events. The precise molecular mechanisms by which IS causes endothelial dysfunction are unknown. We tested the hypothesis that IS negatively influences properties of endothelial cells, such as migration and tube formation, by depleting nitric oxide (NO) bioavailability, and that an NO donor can reverse these inhibitory effects. IS inhibited human umbilical vein endothelial cell (HUVEC) migration and formation of tubes on matrigel. Mechanistically, IS inhibited VEGF-induced NO release from HUVECs. An NO donor, SNAP, reversed IS-mediated inhibition of HUVEC migration as well as tube-formation. IS inhibited ERK 1/2 MAP kinase activity in a dose-dependent manner, but this was preserved by SNAP. Inhibition of ERK 1/2 with a pharmacological inhibitor (U0126) decreased HUVEC migration and tube formation; these effects too were prevented by SNAP. Further, IS stimulated activation of myosin light chain (MLC), potentially stimulating endothelial contractility, while SNAP decreased MLC activation. Thus, we conclude that the negative effects of IS on endothelial cells are prevented, to a major extent, by NO, via its divergent actions on ERK MAP kinase and MLC. |
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Keywords: | Indoxyl sulfate Endothelial cell migration Nitric oxide ERK MAP kinase Myosin light chain |
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