ABSTRACT

Background: The tricarboxylic (TCA) acid cycle provides the energy needed for regulatory functions in the cardio-renal system. Recently, a genetic defect in the TCA cycle enzyme, fumarase hydratase, altered L-arginine metabolism and exacerbated hypertension in salt-sensitive rats. This study evaluated the effect of fumarate and its possible link to L-arginine metabolism in deoxycorticosterone (DOCA)-salt hypertension, a non-genetic model of hypertension.Method: Hypertension was induced with DOCA (25 mg/kg s.c, twice weekly) + 1% NaCL in uninephrectomised rats placed on fumarate (1 g/L, ad libitum). Blood pressure was measured in conscious rats via carotid cannulation. Biochemical and western blot analyses were carried out on kidney fractions.Results: Fumarate reduced mean blood pressure (198 ± 5 vs 167 ± 7 mmHg, p < .01), increased nitric oxide levels in the renal cortex (36.1 ± 2 vs 61.3 ± 4 nM/µg) and medulla (27.4 ± 1 vs 54.1 ± 2 nM/µg) of DOCA-salt rats (p < .01). Consistent with this, arginase activity was reduced (threefold) in the renal medulla but not cortex of DOCA-salt rats. Fumarate increased superoxide dismutase activity in the medulla (p < .001) of DOCA-hypertensive rats. However, catalase activity was exacerbated by fumarate in both renal cortex (4.5 ± 1 vs 11.2 ± 1) and medulla (3.7 ± 1 vs 16.3 ± 1 units/mg) of DOCA-salt rats (p < .001). Proteinuria (64.6%), kidney injury molecule-1 expression and kidney weight were reduced in DOCA-hypertensive rats treated with fumarate (p< .05). However, there was a paradoxical increase in TGF-β expression in fumarate-treated DOCA-salt rats. Conclusion: These data show that fumarate attenuated hypertension, renal injury and improved the redox state of the kidney in DOCA/salt hypertension by mechanisms involving selective reduction of L-arginine metabolism.

摘要

背景：三羧酸 (TCA) 酸循环提供了心肾系统调节功能所需的能量。最近，TCA 循环酶、延胡索酶水合酶的遗传缺陷改变了 L-精氨酸代谢并加剧了盐敏感大鼠的高血压。本研究评估了富马酸盐的作用及其与脱氧皮质酮 (DOCA)-盐高血压（一种非遗传性高血压模型）中 L-精氨酸代谢的可能联系。方法：用 DOCA（25 mg/kg sc，每周两次）+ 1% NaCL 在未切除肾的大鼠中使用富马酸盐（1 g/L，随意）诱导高血压。通过颈动脉插管在有意识的大鼠中测量血压。对肾脏部分进行生化和蛋白质印迹分析。结果：富马酸盐降低平均血压 (198 ± 5 vs 167 ± 7 mmHg, p <  .01)，增加肾皮质 (36.1 ± 2 vs 61.3 ± 4 nM/µg) 和髓质 (27.4 ± 1 vs 54.1 ± 2 nM/µg) DOCA 盐大鼠 ( p <  .01)。与此一致，DOCA-盐大鼠的肾髓质中精氨酸酶活性降低（三倍），但皮质中没有。富马酸盐增加 DOCA 高血压大鼠髓质中的超氧化物歧化酶活性 ( p <  .001)。然而，在 DOCA-salt 大鼠的肾皮质 (4.5 ± 1 vs 11.2 ± 1) 和髓质 (3.7 ± 1 vs 16.3 ± 1 units/mg) 中，过氧化氢酶活性被延胡索酸加剧 ( p < .001)。富马酸盐治疗的 DOCA 高血压大鼠的蛋白尿（64.6%）、肾损伤分子 1 的表达和肾脏重量降低（p < .05）。然而，富马酸盐处理的 DOCA 盐大鼠中 TGF-β 表达反常增加。结论：这些数据表明，富马酸盐通过选择性降低 L-精氨酸代谢的机制减轻 DOCA/盐高血压中的高血压、肾损伤并改善肾脏的氧化还原状态。