Integration of purinergic and angiotensin II receptor function in renal vascular responses and renal injury in angiotensin II-dependent hypertension

Abstract

Glomerular arteriolar vasoconstriction and tubulointerstitial injury are observed before glomerular damage occurs in models of hypertension. High interstitial ATP concentrations, caused by the increase in arterial pressure, alter renal mechanisms involved in the long-term control of blood pressure, autoregulation of glomerular filtration rate and blood flow, tubuloglomerular feedback (TGF) responses, and sodium excretion. Elevated ATP concentrations and augmented expression of P2X receptors have been demonstrated under a genetic background or induction of hypertension with vasoconstrictor peptides. In addition to the alterations of the microcirculation in the hypertensive kidney, the vascular actions of elevated intrarenal angiotensin II levels may be mitigated by the administration of broad purinergic P2 antagonists or specific P2Y12, P2X1, and P2X7 receptor antagonists. Furthermore, the prevention of tubulointerstitial infiltration with immunosuppressor compounds reduces the development of salt-sensitive hypertension, indicating that tubulointerstitial inflammation is essential for the development and maintenance of hypertension. Inflammatory cells also express abundant purinergic receptors, and their activation by ATP induces cytokine and growth factor release that in turn contributes to augment tubulointerstitial inflammation. Collectively, the evidence suggests a pathophysiological activation of purinergic P2 receptors in angiotensin-dependent hypertension. Coexistent increases in intrarenal angiotensin II and activates Ang II AT1 receptors, which interacts with over-activated purinergic receptors in a complex manner, suggesting convergence of their post-receptor signaling processes.

Keywords: AT1 receptor antagonists; ATP; Angiotensin II; Hypertension; P2X antagonists; Purinergic P2X receptors; Renal hemodynamics.

Fig. 1

Renal hemodynamics in rats that received 14 days of Angiotensin II (Ang II) (435 ng/kg/min) during an acute infusion of P2X1 antagonist (NF449) and a P2X7 antagonist (A438079). Only the groups that received Ang II and the AngII + antagonists are shown. The dash line represents the normal values obtained in a Sham rat + vehicle. As observed, the groups that received the antagonists of P2X1 or P2X7 showed a significant decrease of afferent and efferent arteriolar resistances (*< from 0.05 to 0.01) the leads to a significant increase in renal plasma flow; as a consequence of these changes, the single-nephron glomerular filtration rate returned to near normal values, similar to that of the Sham rat. These data clearly demonstrate that in the Ang II-dependent hypertension, the renal vasoconstriction induced by Ang II is associated with an important P2X1 and P2X7 receptor-mediated contribution. In addition, these findings suggest a convergence of their post-receptor signaling pathways

Fig. 2

Proposed mechanism for the effect of the Ang II infusion during 14 days and the P2X1 and P2X7 induced vasoconstriction. Ang II produces systemic hypertension and a rise of interstitial fluid concentrations of ATP as well as Ang II. Renal vasoconstriction is induced by both, a direct effect of Ang II and as a result of the regulatory response to hypertension. Glomerular hemodynamics shows an increase in afferent and efferent resistances (AR, ER) which leads to a decrease of renal blood flow (GBF) and a reduced filtration coefficient (KF); all these changes result in a fall of the single-nephron glomerular filtration rate (SNGFR). The dotted lines represent the values in Sham rats + vehicle for comparison. These alterations induce renal ischemia leading to an overexpression of P2X receptors in the smooth muscle cells of the intrarenal arterioles. Concomitantly, tubulointerstitial inflammatory cell infiltration results and intrarenal ATP is elevated leading to activation of P2X receptors in the intrarenal arteries and on the surface of the inflammatory cells. Collectively, these changes results in cytokines, growth and chemoattractant factors production, which exacerbate the inflammatory infiltration and intensify renal vasoconstriction. Oxidative stress, increases of adenosine (ADO), decreases in nitric oxide (NO), increases in local production of Ang II, and stimulation of the sympathetic tone (SNS) occur. These alterations modify sodium excretion and impair natriuresis, resulting in decreased Na⁺ excretion relative to the expected for the elevation of blood pressure

Fig. 3

Potential synergic interactions between purinergic P2X receptors and AT1R receptors. ATP-activation of P2X receptors opens the ligand-gated Na⁺/Ca²⁺ channel, inducing both, an increase of Ca²⁺ concentration within the cytoplasm and local membrane depolarization. As a consequence, the voltage-gated Ca²⁺ channels (VGCC) adopts its open conformation that contributes to further increase the Ca²⁺ concentrations. Simultaneously, the stimulation of AT1R by Ang II activates the phospholipase C (PLC) and the RhoA/ROCK pathways. PLC pathway leads to inositol-1,4,5-triphosphate (IP3) formation. IP3 in turn induces the opening of the ligand-gated Ca²⁺ channels (IP3R) in the endoplasmic reticulum. The increase of the Ca²⁺ concentration in the cytosol results in a positive feedback of the ryanodine receptor (RyR). The overall effect of the interaction of ATP and Ang II with their corresponding receptors is a conveyance leading to an increase of Ca²⁺ concentration in the cytosol, enough to induce muscular contraction with the consequent reduction of the arteriolar diameter. On the other hand, the RhoA/ROCK pathway leads to phosphorylation of myosin phosphatase target subunit (P-MYPT) thus inhibiting the activity of myosin light chain phosphatase (MLCP), with the consequent vascular smooth muscle cell (VSMC) contractility