Immunosuppression preserves renal autoregulatory function and microvascular P2X₁ receptor reactivity in ANG II-hypertensive rats

Abstract

DM, Inscho EW.Immunosuppression preserves renal autoregulatory function and microvascular P2X1 receptor reactivity in ANG II-hypertensive rats. Am J Physiol Renal Physiol 304: F801-F807, 2013. First published December 26, 2012 doi:10.1152/ajprenal.00286.2012.-Autoregulation is critical for protecting the kidney against arterial pressure elevation and is compromised in some forms of hypertension. Evidence indicates that activated lymphocytes contribute importantly to cardiovascular injury in hypertension. We hypothesized that activated lymphocytes contribute to renal vascular dysfunction by impairing autoregulation and P2X1 receptor signaling in ANG II-infused hypertensive rats. Male Sprague-Dawley rats receiving ANG II infusion were treated with a lymphocyte proliferation inhibitor, mycophenolate mofetil (MMF) for 2 wk. Autoregulation was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. ANG II-treated rats exhibited impaired autoregulation. At the single vessel level, pressure-mediated afferent arteriolar vasoconstriction was significantly blunted (P Ͻ 0.05 vs. control rats). At the whole kidney level, renal blood flow passively decreased as renal perfusion pressure was reduced. MMF treatment did not alter the ANG II-induced hypertensive state; however, MMF did preserve autoregulation. The autoregulatory profiles in both in vitro or in vivo settings were similar to the responses from control rats despite persistent hypertension. Autoregulatory responses are linked to P2X1 receptor activation. Accordingly, afferent arteriolar responses to ATP and the P2X1 receptor agonist ␤,␥-methylene ATP were assessed. ATP-or ␤,␥-methylene ATP-induced vasoconstriction was significantly attenuated in ANG II-infused hypertensive rats but was normalized by MMF treatment. Moreover, MMF prevented elevation of plasma transforming growth factor-␤1 concentration and lymphocyte and macrophage infiltration in ANG II-infused kidneys. These results suggest that anti-inflammatory treatment with MMF prevents lymphocyte infiltration and preserves autoregulation in ANG II-infused hypertensive rats, likely by normalizing P2X 1 receptor activation. autoregulation; inflammation; renal blood flow; mycophenolate mofetil; lymphocytes; afferent arteriole EFFICIENT RENAL AUTOREGULATORY function is critical for controlling renal perfusion and for maintaining stable glomerular capillary pressure in the face of arterial pressure (AP) fluctuations. Renal autoregulation is accomplished by precise adjustments of preglomerular resistance. A decline in afferent arteriolar autoregulatory efficiency renders downstream glomerular capillaries vulnerable to glomerular capillary hypertension. Prolonged glomerular hypertension can lead to glomerulosclerosis and chronic renal failure. Studies from both hypertensive human subjects and animal models indicate that reduced autoregulatory efficiency can precede renal structural changes, particularly in African Americans (27). This suggests that...

Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

“…49 It requires approximately 10 pM of endothelin-1, 6 nM of angiotensin II, 70 nM of S1P, 200 nM of arginine vasopressin, 300 nM of NE, and 100 mM of ATP to achieve a 25% reduction of afferent arteriolar diameters. The concentration of S1P (70 nM) required for this change is in the middle of those often vasoconstrictors, suggesting that biologic behavior of S1P is similar to a number of other important vasoconstrictors.…”

“…The details of the surgical process were previously described. 49 Briefly, rats were anesthetized with pentobarbital (50 mg/kg intraperitoneally) and the left carotid artery and femoral vein were cannulated to monitor arterial pressure and to deliver drugs, respectively. RBF from the left kidney was measured using an ultrasonic flow probe (Transonic Systems, Inc., Ithaca, NY).…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…In contrast, P2X 1 receptor-mediated vasoconstriction of afferent arterioles in the rat kidney is attenuated in Ang-II-dependent hypertension (Inscho, 2009). Immunosuppression preserves renal autoregulatory function and microvascular P2X 1 receptor reactivity in Ang-IIhypertensive rats (Guan et al, 2013). The sensitivity of contractile responses to a,b-meATP, likely involving P2X 1 receptors, was also significantly reduced in isolated subcutaneous veins, but not arteries, from hypertensive patients (Lind et al, 1997).…”

Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension

“…Mice lacking ATP-sensitive P2X 1 receptors exhibit impaired autoregulatory responses (32)(33)(34)44). In addition, afferent arteriolar reactivity to P2X 1 receptor activation is markedly attenuated in ANG-II hypertensive rats, and this blunted reactivity can be preserved by prevention of lymphocyte activation (25). Whether or not P2X 1 and P2Y 12 receptors interact is unclear, but these data, combined with the data provided in the present report, suggest that broader consideration should be given to the role chronic inflammation plays in altering renal autoregulatory efficiency in hypertension and how that might impact hypertensioninduced renal injury.…”

“…Acute administration of TGF-␤ impairs afferent arteriolar autoregulatory vasoconstriction (53). Chronic use of a general anti-inflammatory agent, pentosan polysulfate, or a lymphocyte antiproliferative drug, mycophenolate mofetil, prevented the increase in plasma TGF-␤ and preserved autoregulation in ANG II-infused hypertensive rats without lowering AP (24,25). Monocyte chemoattractant protein-1 receptor blockade in an ANG II ϩ high-salt hypertension model improved autoregulatory reactivity despite persistent hypertension (15).…”