Alt-sensitive hypertension, AT1 receptor blockade ameliorates cardiac or renal dysfunction in these rats, suggesting an important role for RAS in the development of end-organ injury in salt-sensitive 15 hypertension. ,16 In the current BL-8040 dose studies, we observed increased expression of the phosphorylated form of ETS-1 in hypertensive DS rats that was significantly reduced by RAS blockade with ARB, suggesting that increased RAS activation mediates increased ETS-1 phosphorylation and activation in hypertensive DS rats. To determine the role of ETS-1 in the pathogenesis of renal injury in salt-sensitive hypertension, we used a DN ETS-1 peptide that competes for DNA binding with ETS-1 but does not initiate gene transcription. In our studies, we observed that ETS-1 blockade reduced ETS-1 phosphorylation at T38; these findings are consistent with a positive feedback of ETS-1 on its own activation as has been previously described. ETS-1 blockade resulted in significant reductions in GIS, fibronectin expression, proteinuria, and macrophage infiltration but had no significant effect on interstitial fibrosis. RAS blockade also reduced GIS, proteinuria, and macrophage infiltration and had a no significant effect on fibronectin or fibrosis. By contrast, concomitant ETS-1 and RAS blockade had additive effects on all parameters examined. In addition, we observed that ETS-1 blockade resulted in a significant reduction in the urinary excretion of TGF-, suggesting that ETS-1 may be a direct regulator of TGF- in hypertensive DS rats. By contrast, RAS blockade did not modify the urinary excretion of TGF-, indicating that other pathways independent of RAS participate in the production of TGF- in hypertensive DS rats. Both ETS-1 blockade and RAS blockade had small effects on blood pressure as measured by radiotelemetry; however, rats with ETS-1 and RAS blockade had blood pressures that were similar to those from rats on a normal-salt diet, indicating that ETS-1 may also be playing a role in blood pressure regulation either directly or indirectly. In addition, these findings suggest that the additional beneficial effects of concomitant ETS-1 and RAS blockade are in large part due to their effects on blood pressure. To better understand the interaction between RAS and ETS-1, we measured the expression of some of main components of RAS in the different experimental groups. As previously shown by us and others, hypertensive DS rats had significant increases in the urinary excretion of angiotensinogen and intrarenal concentration of Ang II indicative of increased RAS activation. Both ETS-1 and RAS blockade induced significant reductions in the urinary excretion of angiotensinogen and tissue levels of Ang II. In addition, concomitant ETS-1 and RAS blockade further reduced the urinary excretion of angiotensinogen. These findings suggest that ETS-1 also plays a role in the regulation of the RAS, the mechanisms by whichAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptHypertension. Author manuscript; Pan-RAS-IN-1 cost available in PMC 2016 June 08.Feng et al.PageETS-1 could be modulating RAS activity are unclear and are the subject of active investigation in our laboratory. Perspective In these studies, we have unveiled the role of the transcription factor ETS-1 as a mediator of renal injury in salt-sensitive hypertension. In addition, we determined that the activation of RAS mediates ETS-1 phosphorylation in hypertensive salt-sensitive rats and that concomitant RAS an.Alt-sensitive hypertension, AT1 receptor blockade ameliorates cardiac or renal dysfunction in these rats, suggesting an important role for RAS in the development of end-organ injury in salt-sensitive 15 hypertension. ,16 In the current studies, we observed increased expression of the phosphorylated form of ETS-1 in hypertensive DS rats that was significantly reduced by RAS blockade with ARB, suggesting that increased RAS activation mediates increased ETS-1 phosphorylation and activation in hypertensive DS rats. To determine the role of ETS-1 in the pathogenesis of renal injury in salt-sensitive hypertension, we used a DN ETS-1 peptide that competes for DNA binding with ETS-1 but does not initiate gene transcription. In our studies, we observed that ETS-1 blockade reduced ETS-1 phosphorylation at T38; these findings are consistent with a positive feedback of ETS-1 on its own activation as has been previously described. ETS-1 blockade resulted in significant reductions in GIS, fibronectin expression, proteinuria, and macrophage infiltration but had no significant effect on interstitial fibrosis. RAS blockade also reduced GIS, proteinuria, and macrophage infiltration and had a no significant effect on fibronectin or fibrosis. By contrast, concomitant ETS-1 and RAS blockade had additive effects on all parameters examined. In addition, we observed that ETS-1 blockade resulted in a significant reduction in the urinary excretion of TGF-, suggesting that ETS-1 may be a direct regulator of TGF- in hypertensive DS rats. By contrast, RAS blockade did not modify the urinary excretion of TGF-, indicating that other pathways independent of RAS participate in the production of TGF- in hypertensive DS rats. Both ETS-1 blockade and RAS blockade had small effects on blood pressure as measured by radiotelemetry; however, rats with ETS-1 and RAS blockade had blood pressures that were similar to those from rats on a normal-salt diet, indicating that ETS-1 may also be playing a role in blood pressure regulation either directly or indirectly. In addition, these findings suggest that the additional beneficial effects of concomitant ETS-1 and RAS blockade are in large part due to their effects on blood pressure. To better understand the interaction between RAS and ETS-1, we measured the expression of some of main components of RAS in the different experimental groups. As previously shown by us and others, hypertensive DS rats had significant increases in the urinary excretion of angiotensinogen and intrarenal concentration of Ang II indicative of increased RAS activation. Both ETS-1 and RAS blockade induced significant reductions in the urinary excretion of angiotensinogen and tissue levels of Ang II. In addition, concomitant ETS-1 and RAS blockade further reduced the urinary excretion of angiotensinogen. These findings suggest that ETS-1 also plays a role in the regulation of the RAS, the mechanisms by whichAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptHypertension. Author manuscript; available in PMC 2016 June 08.Feng et al.PageETS-1 could be modulating RAS activity are unclear and are the subject of active investigation in our laboratory. Perspective In these studies, we have unveiled the role of the transcription factor ETS-1 as a mediator of renal injury in salt-sensitive hypertension. In addition, we determined that the activation of RAS mediates ETS-1 phosphorylation in hypertensive salt-sensitive rats and that concomitant RAS an.
