Cytochrome P450-dependent renal arachidonic acid metabolism in desoxycorticosterone acetate-salt hypertensive mice
Cytochrome P450-dependent renal arachidonic acid metabolism in desoxycorticosterone acetate-salt hypertensive mice
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DOI：
10.1161/01.hyp.36.4.610
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发表时间：
2000-10-01
期刊：
影响因子：
8.3
通讯作者：
Schunck, WH
中科院分区：
文献类型：
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作者：
Honeck, H;Gross, V;Schunck, WH
细胞色素P450（P450）依赖的花生四烯酸代谢产物可作为调节血管张力和肾功能的介质。我们研究了花生四烯酸羟化酶的活动，肾微粒体从血压正常的NMRI小鼠，醋酸去氧皮质甾酮（DOCA）盐高血压小鼠，和DOCA盐小鼠治疗的洛伐他汀或苯扎贝特，这两个改善血流动力学在这个模型中。对照肾微粒体的花生四烯酸羟化酶活性为175+/-12 pmol（.）min（-1）（.）mg（-1）。形成的代谢产物为20-和19-羟基花生四烯酸，分别占总羟基化的约80%和约20%。用DOCA-盐处理导致羟化酶活性显著降低（至84+/-4pmol（.）min（-1）（.）mg（-1））的总微粒体P450含量和免疫检测Cyp 4a蛋白的减少。洛伐他汀对这些变量没有影响，而苯扎贝特使花生四烯酸羟化酶活性增加到163 +/- 12 pmol（.）min（-1）。mg（-1）。Cyp 4a-10、12和14探针原位杂交显示Cyp 4a-14是苯扎贝特诱导最强的P450亚型。表达集中在皮质髓质交界处，主要位于近端小管。总之，这些结果表明，DOCA盐高血压小鼠的肾脏产生20-羟基花生四烯酸的能力受损。此外，苯扎贝特可能通过恢复P350依赖性花生四烯酸羟化酶活性来改善该模型的血流动力学。另一方面，洛伐他汀通过P450非依赖性机制发挥其作用。
Cytochrome P450 (P450)-dependent arachidonic acid metabolites may act as mediators in the regulation of vascular tone and renal function. We studied arachidonic acid hydroxylase activities in renal microsomes from normotensive NMRI mice, desoxycorticostetone acetate (DOCA)-salt hypertensive mice, and DOCA-salt mice treated with either lovastatin or bezafibrate, both of which improve hemodynamics in this model. Control renal microsomes had arachidonic acid hydroxylase activities of 175+/-12 pmol (.) min(-1) (.) mg(-1). The metabolites formed were 20- and 19-hvdroxyarachidonic acid, representing approximate to 80% and approximate to 20% of the total hydroxylation. Treatment with DOCA-salt resulted in significantly decreased hydroxylase activities (to 84+/-4 pmol (.) min(-1) (.) mg(-1)) of the total microsomal P450 content and a decrease in immunodetectable Cyp4a proteins. Lovastatin had no effect on these variables, whereas bezafibrate increased arachidonic acid hydroxylase activities to 163 +/- 12 pmol (.) min(-1) . mg(-1). In situ hybridization with probes for Cyp4a-10, 12, and 14 revealed that Cyp4a-14 was the P450 isoform most strongly induced by bezafibrate. The expression was concentrated in the cortical medullary junction and was localized predominantly in the proximal tubules. In conclusion, these results suggest that the capacity to produce 20-hydroxyarachidonic acid is impaired in the kidneys of DOCA-salt hypertensive mice. Furthermore, bezafibrate may ameliorate hemodynamics in this model by restoring P350-dependent arachidonic acid hydroxylase activities. Lovastatin, on the other hand, exerts its effects via P450-independent mechanisms.