瞬时受体电位香草酸亚型1受体及C-C趋化因子受体2在盐敏感性高血压所致肾脏损害中的作用

Role of Transient Receptor Potential Vanilloid Type 1 and C-C Chemokine Receptor 2 in Renal Injury Induced by Salt-sensitive Hypertension

目的观察瞬时受体电位香草酸亚型1(TRPV1)受体基因缺陷和C-C趋化因子受体2(CCR2)阻断剂对盐敏感性高血压所致肾脏损害的影响。方法野生型和TRPV1基因缺陷(TRPV1-/-)小鼠通过切除左侧肾脏、皮下包埋醋酸脱氧皮质酮(DOCA)和饮用盐水建立DOCA-盐高血压模型。DOCA-盐高血压组(野生型和TRPV1-/-小鼠n均=8)和DOCA-盐高血压-RS504393组(野生型和TRPV1-/-小鼠n均=8)分别皮下注射溶媒和特异性的CCR2阻断剂RS504393,假手术组野生型和TRPV1-/-小鼠(n均=7)仅左肾切除和给予正常饮用水。实验共4周,实验期间和结束时分别检测动脉收缩压、24 h尿白蛋白排泄量、尿8-异构前列腺素排泄量和肌酐清除率。取右肾进行病理组织学分析,比较肾小球硬化指数、肾小管间质损伤程度及单核/巨噬细胞浸润程度。结果与相应的假手术组比较,野生型DOCA-盐高血压组和TRPV1-/-DOCA-盐高血压组的血压显著升高,24 h尿白蛋白和尿8-异构前列腺素排泄量显著增加,肌酐清除率显著下降(P均<0.05);肾小球硬化指数和肾小管间质损伤程度显著升高,且单核/巨噬细胞浸润数量显著增加(P均<0.05)。除血压外,TRPV-/-DOCA-盐高血压组上述病理变化均显著高于野生型DOCA-盐高血压组(P均<0.05)。RS504393处理组的上述异常变化显著弱于相应的DOCA-盐高血压组(P均<0.05)。除假手术组外,DOCA-盐高血压组和DOCA-盐高血压-RS504393组的血压差异均无统计学意义(P均>0.05)。结论在野生型和TRPV1-/-小鼠中,CCR2阻断剂均可抑制DOCA-盐高血压所致的肾脏损害及肾内单核/巨噬细胞浸润,并且其抑制作用在TRPV1-/-小鼠中明显增强,提示TRPV1受体可能通过抑制CCR2所介导的单核/巨噬细胞浸润来减轻盐敏感性高血压所造成的肾脏损害。

Objective To determine the effects of transient receptor potential vanilloid type 1 （TRPV1） channel ablation and a chemokine receptor 2 （CCR2） antagonist on salt-sensitive hypertension-induced renal inju- ry. Methods Wild-type （WT） and TRPVI-null mutant （TRPV1-/） mice were subjected to uninephrectomy and deoxycorticosterone acetate （DOCA） -salt treatment for 4 weeks with or without a CCR2 antagonist, RS504393 （n = 8 for all the 4 groups） . Sham WT and TRPVl/-mice （both n = 7 ） underwent uninephrectomy without receiving DOCA and saline. Systolic blood pressure, urinary excretion of albumin, 8-isoprostane and creatinine clearance for 24 hours were assayed during the experimental period and at the end of the d-week treat- ment. The morphological analysis was performed in renal histological sections, including glomerulosclerosis, tu- bulointerstitial injury, and monocyte/macrophage infiltration. Results Compared to the corresponding control mice, DOCA-salt treatment in both WT and TRPV1-/-mice led to increased systolic blood pressure （SBP）, en- hanced urinary excretion of albumin and 8-isoprostane, decreased creatinine clearance, increased glomeruloscle- rosis and tubulointerstitial injury associated with enhanced monocyte/macrophage infiltration （ all P 〈 0.05）, all of which were much more severe in TRPV1 -/-mice compared to WT mice with the exception of blood pressure （ all P 〈 0. 05 ） . RS5043943 attenuated DOCA-sah-induced changes in renal function and morphology in WT and TRPV1-/- mice （all P 〈 0.05 ） . There was no difference in blood pressure among DOCA-salt WT and TRPV1 -/- mice with or without RS505393 with the exception of sham WT and TRPVl / mice （all P 〉 0.05） . Conclu- sions CCR2 antagonist inhibits DOCA-salt-induced renal injury and monocyte/macrophage infiltration in WT and TRPV1 -/-mice with the greater in the latter strain. Activation of TRPV1 attenuates salt-sensitive hy- pertension-induced renal injury possibly via inhibition of CCR2-induced monocyte/macrophage infiltration.