Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats.
Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats.
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肾素原独立引起 cyp1a1-肾素原转基因大鼠的高血压以及肾和心脏纤维化
DOI：
10.1042/cs20171659
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发表时间：
2018-06-29
期刊：
影响因子：
--
通讯作者：
Huang Y
中科院分区：
文献类型：
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作者：
Zhou G;Wu J;Gu C;Wang B;Abel ED;Cheung AK;Huang Y
糖尿病患者血浆肾素原水平普遍升高，似乎可预测糖尿病肾病的发展。然而，前肾素的病理作用尚不清楚。在本研究中，一个转基因，诱导，肝前肾素过表达大鼠模型的产生和前肾素在器官损伤的影响进行了检查。将四组大鼠（cyp 1a 1前肾素转基因雄性和雌性大鼠以及非转基因同窝仔）分配为接受含有0.3%转基因诱导剂吲哚-3-甲醇（I3 C）的饲料4周。在喂食I3 C饲料的转基因大鼠中，血浆前肾素浓度增加，平均动脉压（MAP）从80 ± 18（mmHg）增加至138 ± 17（mmHg），而肾脏前肾素/肾素蛋白表达无变化。通过Western印迹分析进一步观察血浆和尿液样品中完整的原肾素，而不是肾素。重要的是，高水平前肾素的转基因大鼠发生蛋白尿、肾小球和肾小管间质纤维化，与转化生长因子β（TGFβ）1（TGFβ1）、纤溶酶原激活物抑制剂-1（派-1）、胶原和纤连蛋白（FN）表达增加相关。这些大鼠还表现出心脏肥大，通过超声心动图确定，心脏重量与体重的比值（HW/BW）升高。心肌间质和血管周围胶原含量显著增加，同时伴有心钠素（ANP）、脑钠素（BNP）、β-肌球蛋白重链（β-MHC）、TGFβ1、派-1和胶原mRNA含量的增加。此外，在prenin过度表达大鼠中，p-NF-κB-p65和单核细胞趋化蛋白-1（MCP-1）、NAPDH氧化酶、丙二醛（MDA）和8-异前列腺素（8-IP）、p-ERK、p-β-catenin和p-Akt的肾蛋白水平显著增加。这些结果表明，未转化为肾素的原肾素通过诱导炎症、氧化应激和ERK、β-连环蛋白和Akt介导的信号引起高血压、肾和心脏纤维化。
Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor β (TGFβ) 1 (TGFβ1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, β-catenin, and Akt-mediated signals.