TY - JOUR
T1 - Pentosan polysulfate treatment preserves renal autoregulation in ANG II-infused hypertensive rats via normalization of P2X 1 receptor activation
AU - Guan, Zhengrong
AU - Fuller, Barry S
AU - Yamamoto, Tatsuo
AU - Cook, Anthony K.
AU - Pollock, Jennifer S.
AU - Inscho, Edward W.
PY - 2010/5/1
Y1 - 2010/5/1
N2 - Inflammatory factors are elevated in animal and human subjects with hypertension and renal injury. We hypothesized that inflammation contributes to hypertension-induced renal injury by impairing auto-regulation and microvascular reactivity to P2X 1 receptor activation. Studies were conducted in vitro using the blood-perfused juxtamedullary nephron preparation. Rats receiving ANG II (60 ng/min) infusion were treated with the anti-inflammatory agent pentosan polysulfate (PPS) for 14 days. The magnitude and progression of hypertension were similar in ANG II and ANG II+PPS-treated rats (169 ± 5 vs. 172 ± 2 mmHg). Afferent arterioles from control rats exhibited normal autoregulatory behavior with diameter decreasing from 18.4 ± 1.6 to 11.4 ± 1.7 μm when perfusion pressure was increased from 70 to 160 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in ANG II-treated rats, and diameter remained essentially unchanged over the range of perfusion pressures. However, ANG II-treated rats receiving PPS exhibited normal autoregulatory behavior compared with ANG II alone rats. Arteriolar reactivity to ATP and β,γ-methylene ATP was significantly reduced in ANG II hypertensive rats compared with controls. Interestingly, PPS treatment preserved normal reactivity to P2 and P2X 1 receptor agonists despite the persistent hypertension. The maximal vasoconstriction was 79 ± 3 and 81 ± 2% of the control diameter for ATP and β,γ-methylene ATP, respectively, similar to responses in control rats. PPS treatment significantly reduced α-smooth muscle actin staining in afferent arterioles and plasma transforming growth factor-β1 concentration in ANG II-treated rats. In conclusion, PPS normalizes autoregulation without altering ANG II-induced hypertension, suggesting that inflammatory processes reduce P2X 1 receptor reactivity and thereby impair autoregulatory behavior in ANG II hypertensive rats.
AB - Inflammatory factors are elevated in animal and human subjects with hypertension and renal injury. We hypothesized that inflammation contributes to hypertension-induced renal injury by impairing auto-regulation and microvascular reactivity to P2X 1 receptor activation. Studies were conducted in vitro using the blood-perfused juxtamedullary nephron preparation. Rats receiving ANG II (60 ng/min) infusion were treated with the anti-inflammatory agent pentosan polysulfate (PPS) for 14 days. The magnitude and progression of hypertension were similar in ANG II and ANG II+PPS-treated rats (169 ± 5 vs. 172 ± 2 mmHg). Afferent arterioles from control rats exhibited normal autoregulatory behavior with diameter decreasing from 18.4 ± 1.6 to 11.4 ± 1.7 μm when perfusion pressure was increased from 70 to 160 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in ANG II-treated rats, and diameter remained essentially unchanged over the range of perfusion pressures. However, ANG II-treated rats receiving PPS exhibited normal autoregulatory behavior compared with ANG II alone rats. Arteriolar reactivity to ATP and β,γ-methylene ATP was significantly reduced in ANG II hypertensive rats compared with controls. Interestingly, PPS treatment preserved normal reactivity to P2 and P2X 1 receptor agonists despite the persistent hypertension. The maximal vasoconstriction was 79 ± 3 and 81 ± 2% of the control diameter for ATP and β,γ-methylene ATP, respectively, similar to responses in control rats. PPS treatment significantly reduced α-smooth muscle actin staining in afferent arterioles and plasma transforming growth factor-β1 concentration in ANG II-treated rats. In conclusion, PPS normalizes autoregulation without altering ANG II-induced hypertension, suggesting that inflammatory processes reduce P2X 1 receptor reactivity and thereby impair autoregulatory behavior in ANG II hypertensive rats.
KW - Afferent arteriole
KW - P2X purinoceptor
KW - Pentosan polysulfate
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U2 - 10.1152/ajprenal.00743.2009
DO - 10.1152/ajprenal.00743.2009
M3 - Article
C2 - 20200092
AN - SCOPUS:77951518336
VL - 298
SP - F1276-F1284
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 5
ER -