Wang Youping, Wang Donna H
Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
Am J Physiol Renal Physiol. 2009 Dec;297(6):F1550-9. doi: 10.1152/ajprenal.00012.2009. Epub 2009 Sep 30.
To test the hypothesis that deletion of the transient receptor potential vanilloid type 1 (TRPV1) channel exaggerates hypertension-induced renal inflammatory response, wild-type (WT) or TRPV1-null mutant (TRPV1(-/-)) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 4 wk. Mean arterial pressure (MAP) determined by radiotelemetry increased in DOCA-salt-treated WT or TRPV1(-/-) mice, whereas there was no difference in MAP between two strains at the baseline or after DOCA-salt treatment. DOCA-salt treatment increased urinary excretion of albumin and 8-isoprostane in both WT and TRPV1(-/-) mice, and the increases were greater in magnitude in the latter strain. Periodic acid-Schiff and Mason's trichrome staining showed that kidneys of DOCA-salt-treated TRPV1(-/-) mice exhibited more severe glomerulosclerosis and tubulointerstitial injury compared with DOCA-salt-treated WT mice. NF-kappaB assay showed that DOCA-salt treatment increased renal activated NF-kappaB concentrations in TRPV1(-/-) mice compared with WT mice. Immunostaining and ELISA assay revealed that DOCA-salt-treated TRPV1(-/-) mice had enhanced renal infiltration of monocyte/macrophage and lymphocyte, as well as increased renal levels of proinflammatory cytokine (TNF-alpha, IL-6) and chemokine (MCP-1) compared with DOCA-salt-treated WT mice. Renal ICAM-1 but not VCAM-1 expression was also greater in DOCA-salt-treated TRPV1(-/-) than WT mice. Dexamethasone (DEXA), an immunosuppressive drug, conveyed a renoprotective effect that was greater in DOCA-salt-treated TRPV1(-/-) compared with WT mice. These data show that renal inflammation is exacerbated in DOCA-salt hypertension when TRPV1 gene is deleted and that the deterioration is ameliorated by DEXA treatment, indicating that TRPV1 may act as a potential regulator of the inflammatory process to lessen renal injury in DOCA-salt hypertension.
为了验证瞬时受体电位香草酸亚型1（TRPV1）通道缺失会加剧高血压诱导的肾脏炎症反应这一假说，对野生型（WT）或TRPV1基因敲除突变体（TRPV1(-/-)）小鼠进行单侧肾切除并给予醋酸脱氧皮质酮（DOCA）-盐处理4周。通过无线电遥测法测定的平均动脉压（MAP）在接受DOCA-盐处理的WT或TRPV1(-/-)小鼠中均升高，而在基线时或DOCA-盐处理后，两品系小鼠的MAP无差异。DOCA-盐处理使WT和TRPV1(-/-)小鼠的白蛋白和8-异前列腺素尿排泄量增加，且后者增加幅度更大。过碘酸-希夫染色和马森三色染色显示，与接受DOCA-盐处理的WT小鼠相比，接受DOCA-盐处理的TRPV1(-/-)小鼠的肾脏表现出更严重的肾小球硬化和肾小管间质损伤。核因子κB检测显示，与WT小鼠相比，DOCA-盐处理使TRPV1(-/-)小鼠肾脏中活化的核因子κB浓度增加。免疫染色和酶联免疫吸附测定显示，与接受DOCA-盐处理的WT小鼠相比，接受DOCA-盐处理的TRPV1(-/-)小鼠的肾脏单核细胞/巨噬细胞和淋巴细胞浸润增强，促炎细胞因子（肿瘤坏死因子-α、白细胞介素-6）和趋化因子（单核细胞趋化蛋白-1）水平升高。接受DOCA-盐处理的TRPV1(-/-)小鼠的肾脏细胞间黏附分子-1（ICAM-1）表达也高于WT小鼠，而血管细胞黏附分子-1（VCAM-1）表达无差异。免疫抑制药物地塞米松（DEXA）在接受DOCA-盐处理的TRPV1(-/-)小鼠中比在WT小鼠中发挥更大的肾脏保护作用。这些数据表明，当TRPV1基因缺失时，DOCA-盐性高血压中的肾脏炎症会加剧，而地塞米松治疗可改善这种恶化情况，表明TRPV1可能作为炎症过程的潜在调节因子，减轻DOCA-盐性高血压中的肾脏损伤。
