Physiological role for P2X1 receptors in renal microvascular autoregulatory behavior

Abstract

This study tests the hypothesis that P2X 1 receptors mediate pressure-induced afferent arteriolar autoregulatory responses. Afferent arterioles from rats and P2X 1 KO mice were examined using the juxtamedullary nephron technique. Arteriolar diameter was measured in response to step increases in renal perfusion pressure (RPP). Autoregulatory adjustments in diameter were measured before and during P2X receptor blockade with NF279 or A 1 receptor blockade with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). Acute papillectomy or furosemide perfusion was performed to interrupt distal tubular fluid flow past the macula densa, thus minimizing tubuloglomerular feedback-dependent influences on afferent arteriolar function. Under control conditions, arteriolar diameter decreased by 17% and 29% at RPP of 130 and 160 mmHg, respectively. Blockade of P2X 1 receptors with NF279 blocked pressuremediated vasoconstriction, reflecting an attenuated autoregulatory response. The A 1 receptor blocker DPCPX did not alter autoregulatory behavior or the response to ATP. Deletion of P2X 1 receptors in KO mice significantly blunted autoregulatory responses induced by an increase in RPP, and this response was not further impaired by papillectomy or furosemide. WT control mice exhibited typical RPPdependent vasoconstriction that was significantly attenuated by papillectomy. These data provide compelling new evidence indicating that tubuloglomerular feedback signals are coupled to autoregulatory preglomerular vasoconstriction through ATP-mediated activation of P2X 1 receptors.

Ectonucleotidases in the kidney

“…No information is yet available concerning NPPs 1 and 2 in the rat. NTPDase8 has been detected in porcine tubules [21], but its exact location is not yet known induce constriction [40]. However, strong evidence also exists for adenosine (acting via A 1 receptors) being the chemical mediator in this response [41,42].…”

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

“…Blockade of P2rx1 receptors or deletion of P2rx1 receptors in knockout mice eliminates pressure-mediated afferent arteriolar contraction. 47 In hypertensive renal disease, pathological changes arise in small arteries in the early stage. 48 So, this ATP-P2X axis might be damaged, which could subsequently lead to down regulation of pressure sensory ability and cause glomerular hypertensive injury.…”

Ca2+ entry following P2X receptor activation induces IP3 receptor‐mediated Ca2+ release in myocytes from small renal arteries

“…Although M3 receptors are linked to a Gq/11/PLC/IP3/Ca 2+ signalling pathway, we hypothesized that in contrast to cardiac muscle, excitation-contraction (E-C) coupling in smooth muscle occurs by Ca 2+ entry through VGCCs, which evokes IP3R-mediated Ca 2+ release via CICR mechanism. This hypothesis needs to be tested in vascular myocytes regulated by ionotropic receptors, which are not coupled to the Gq/11-GTP/PLC/IP3 system.Taking into account the importance of ionotropic P2X receptors (Burnstock, 2007;Surprenant and North, 2009) in the regulation of renal circulation (Malpas and Leonard, 2000;Inscho et al, 2003;Cupples and Braam, 2007;Guan et al, 2007a), we tested our hypothesis on RVSMCs, which, as we have recently demonstrated, express functional monomeric P2X1 and heteromeric P2X1/4 receptors (Harhun et al, 2010). We found that depolarization of RVSMCs following P2X receptor activation induces IP3R-mediated Ca 2+ release from sub-plasmalemmal ('junctional') sarcoplasmic reticulum (jSR), which is activated mainly by Ca 2+ influx through VGCCs.…”