This promotes renal inflammation and renal fibrosis, leading to a decline in renal function that contributes to hypertension. P2X7 and Systemic Vasculature P2X7 expression has been reported in the endothelium and the smooth muscle layer of most of the systemic arterial and venous circulation in human and animal tissues.63C66 In the microvasculature, P2X7 activation has been shown to promote vascular dysfunction through increased oxidative stress and increased endothelial cell permeability and apoptosis. efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders. gene have an overactivated renin-angiotensin-aldosterone system and develop severe hypertension that can be attenuated with angiotensin-converting enzyme inhibitors.47,48 These transgenic rats have increased P2X7 KS-176 expression in the glomeruli in comparison to normotensive rats.46 Other hypertensive models demonstrate similar results, with P2X7 expression significantly increased in the kidney in Ang II (angiotensin II) and deoxycorticosterone acetateCsalt-induced hypertensive rodents, as well as in Dahl salt-sensitive rats.38,49C51 P2X7 receptor silencing decreased renin activity and angiotensin-converting enzyme 1 and 2 expression in the renal cortex, preventing renal dysfunction in a model of diabetic nephropathy.52 In addition, P2X7 antagonism may also reduce the prohypertensive effects of Ang II. Ang II acts as a potent vasoconstrictor of the renal vasculature, and it can alter renal sodium and water handling through increased aldosterone release.53 In rodent models, P2X7 antagonism reduced renal vascular resistance and increased medullary perfusion, resulting in enhanced pressure natriuresis.49,50,54 Menzies et al49 reported a 6-fold increase in KS-176 sodium excretion with P2X7 antagonism, blunting Ang IICinduced BP elevation in rats. In addition, ATP promotes transepithelial sodium transport through epithelial sodium channels, which can be attenuated by Brilliant Blue Ga P2X7 antagonist.55 This, along with increased pressure natriuresis, may account for the increased Na+ excretion associated with P2X7 antagonism.49,50 However, another study found that P2X7 antagonism had no effect on Ang IICinduced BP elevation in rats, although the authors used KS-176 a KS-176 10-fold higher dose of Ang II, which may account for KS-176 the differences observed.50 Overall, these studies provide evidence for a role of P2X7 in the regulation of kidney responses to hypertensive stimuli and support P2X7 as a novel antihypertensive target. Further supporting the beneficial effects of inhibiting P2X7, activation of the receptor itself exerts prohypertensive effects in the kidney. Ang II and aldosterone both increase renal ATP concentrations, with the concentration of renal interstitial ATP strongly correlated with BP increase.56,57 P2X7 activation on the renal vasculature, by elevated ATP, appears to exert a tonic vasoconstrictive effect.49 In addition, P2X7-mediated vasoconstriction of the medullary microcirculation has been shown to cause regional hypoxia promoting vascular GCN5L hypertrophy and renal inflammation.49 Prolonged exposure to elevated extracellular ATP results in P2X7-mediated mesangial, fibroblast, endothelial, and renal tubular cell death, contributing to renal inflammation and fibrosis, as well as promoting endothelial dysfunction.58C62 P2X7 antagonism results in a partially NO-dependent vasodilation of the afferent, efferent, and renal arteries, increasing renal perfusion and reducing renal inflammation and fibrosis.49,50,52,54 P2X7 KO (knockout) or antagonism has also proved effective in preventing renal fibrosis, renal immune cell infiltration, and lowering BP and albuminuria in Dahl salt-sensitive rats and in a deoxycorticosterone acetateCsalt model of hypertension.38,51 In summary, continuous P2X7 activation leads to microvascular dysfunction and regional hypoxia. This promotes renal inflammation and renal fibrosis, leading to a decline in renal function that contributes to hypertension. P2X7 and Systemic Vasculature P2X7 expression has been reported in the endothelium and the smooth muscle layer of most of the systemic arterial and venous circulation in human and animal tissues.63C66 In the microvasculature, P2X7 activation has been shown to promote vascular dysfunction through increased oxidative stress.