Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice
Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice
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DOI：
10.1161/hh1001.091521
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发表时间：
2001-05-25
影响因子：
20.1
通讯作者：
Perella, MA
中科院分区：
文献类型：
--
作者：
Wiesel, P;Patel, AP;Perella, MA
血红素加氧酶（HO）是一种细胞保护酶，可降解血红素（一种有效的氧化剂），产生一氧化碳（一种具有抗炎特性的血管舒张气体）、胆红素（一种来自胆绿素的抗氧化剂）和铁（被铁蛋白螯合）。由于HO及其产物的性质，我们推测HO在血压调节和缺血性损伤中起重要作用。我们使用一肾一夹（1 K1 C）疾病模型研究了HO-1诱导型亚型缺陷小鼠的慢性肾血管性高血压。基线时，野生型（HO-1（+/+））、杂合型（HO-1（+/-））和纯合型（HO-1（-/-））小鼠之间的收缩压无差异。1 K1 C手术后，HO-1（+/+）小鼠发生高血压（140 +/-2 mm Hg）和心脏肥大（心脏重量指数为5.0 +/-0.2 mg/g）与假手术HO-1（+/+）小鼠相比然而，1 K1 C在HO-1（-/-）小鼠中产生更严重的高血压（164 +/-2 mmHg）和心脏肥大（6.9 +/-0.6 mg/g）。与HO-1（+/+）（25%）和HO-1（+/-）（28%）小鼠相比，HO-1（-/-）小鼠在1 K1 C手术后72小时内也经历了高死亡率（56%）。肾功能评估显示，与HO-1（+/-）小鼠相比，HO-1（-/-）小鼠的血浆肌酐显著更高，对1 K1 C HO-1（-/-）小鼠肾脏的组织学分析显示，皮髓质连接处存在广泛的缺血性损伤，而假HO-1（-/-）和1 K1 C HO-1（+/-）小鼠的肾脏表现正常。总之，这些数据表明，HO-1的慢性缺乏不会改变基础血压;然而，在1 K1 C模型中，HO-1的缺乏会导致更严重的肾血管性高血压和心脏肥大。此外，肾动脉夹闭导致缺血性损伤和死亡的急性增加在HO-1的情况下。
Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140 +/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0 +/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108 +/- 5 mm Hg and 4.1 +/-0.1 mg/g, respectively), However, 1K1C produced more severe hypertension (164 +/-2 mmHg) and cardiac hypertrophy (6.9 +/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice, Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice, Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.