Renal autoregulation in P2X₁ knockout mice

Abstract

Autoregulation of renal blood flow is an established physiological phenomenon, however the signalling mechanisms involved remain elusive. Autoregulatory adjustments in preglomerular resistance involve myogenic and tubuloglomerular feedback (TGF) influences. While there is general agreement on the participation of these two regulatory pathways, the signalling molecules and effector mechanisms have not been identified. Currently, there are two major hypotheses being considered to explain the mechanism by which TGF signals are transmitted from the macula densa to the afferent arteriole. The adenosine hypothesis proposes that the released adenosine triphosphate (ATP) is hydrolysed to adenosine and this product stimulates preglomerular vasoconstriction by activation of A(1) receptors on the afferent arteriole. Alternatively, the P2 receptor hypothesis postulates that ATP released from the macula densa directly stimulates afferent arteriolar vasoconstriction by activation of ATP-sensitive P2X(1) receptors. This hypothesis has emerged from the realization that P2X(1) receptors are heavily expressed along the preglomerular vasculature. Inactivation of P2X(1) receptors impairs autoregulatory responses while afferent arteriolar responses to A(1) adenosine receptor activation are retained. Autoregulatory behaviour is markedly attenuated in mice lacking P2X(1) receptors but responses to adenosine A(1) receptor activation remain intact. More recent experiments suggest that P2X(1) receptors play an essential role in TGF-dependent vasoconstriction of the afferent arteriole. Interruption of TGF-dependent influences on afferent arteriolar diameter, by papillectomy or furosemide treatment, significantly attenuated pressure-mediated afferent arteriolar vasoconstriction in wild-type mice but had no effect on the response in P2X(1) knockout mice. Collectively, these observations support an essential role for P2X(1) receptors in TGF-mediated afferent arteriolar vasoconstriction.

Adenosine and Kidney Function

“…It was further proposed that the released ATP itself through activation of purinergic P2 receptors triggers an increase in cytosolic Ca 2ϩ in the extraglomerular mesangium cells and/or the smooth muscle cells of the afferent arteriole, and thus ATP acts as the principal mediator of TGF (22,239). Even though substantial evidence points to a role of ATP and P2X1 receptors in renal autoregulation (142,239), no data have been published that indicate a direct role of a P2 receptor in the TGF response, such as studies with selective receptor antagonists or in knockout mice demonstrating inhibition of macula densa-dependent control of SNGFR. Moreover, Ren et al (279) microperfused rabbit afferent arterioles and attached macula densas simultaneously in vitro and found that adding the P2 purinergic receptor inhibitor suramin to both arteriole lumen and bath did not significantly inhibit the TGF response.…”

ATP as a mediator of macula densa cell signalling

“…As discussed in more detail by Inscho, the kidney is a highly efficient autoregulatory organ and it is generally accepted that the TGF mechanism is responsible, at least in part, for this behaviour [90][91][92][93]. Thus, in response to an increase in blood pressure, there would be a transient elevation in GFR, leading to increased tubular flow into the proximal tubule.…”

“…A more direct means of assessing the role of ATP in autoregulatory responses is the in vitro bloodperfused juxtamedullary nephron preparation. Inscho and coworkers [49,82,87,88,91] found that pressure-induced afferent arteriolar vasoconstriction was attenuated during pharmacological blockade of P2 receptors with suramin, PPADS or the more selective blocker NF-279. Desensitisation of P2 receptors also inhibited pressure-induced autoregulatory adjustments in afferent arteriolar diameter.…”

Mechanisms of renal blood flow autoregulation: dynamics and contributions

“…Autoregulation of renal blood flow (RBF) has long been recognized (153,202). It has since been extensively studied and is well characterized under steady-state conditions as summarized in many excellent review articles (78,87,123,139,168,199). It is thought today, that RBF autoregulation is based on two mechanisms, the myogenic response (MR) and the tubuloglomerular feedback (TGF).…”