Lack of renoprotective effect of chronic intravenous angiotensin-(1-7) or angiotensin-(2-10) in a rat model of focal segmental glomerulosclerosis.
Lack of renoprotective effect of chronic intravenous angiotensin-(1-7) or angiotensin-(2-10) in a rat model of focal segmental glomerulosclerosis.
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DOI：
10.1371/journal.pone.0110083
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Fitzgibbon WR
中科院分区：
文献类型：
--
作者：
Velez JC;Janech MG;Hicks MP;Morinelli TA;Rodgers J;Self SE;Arthur JM;Fitzgibbon WR
无抗血管紧张素（Ang） ii介导的细胞效应可能导致进行性肾小球硬化。虽然Ang- ii可以在肾脏中局部生成，但我们之前发现肾小球足细胞主要将Ang- i （Ang- ii的前体）转化为Ang-(1-7)和Ang-(2-10)，这两种肽独立参与了与Ang- ii相反的生物作用。因此，我们假设Ang-(1-7)和Ang-(2-10)可能对小黄头高血压大鼠（局灶节段性肾小球硬化模型）具有肾保护作用。我们评估了8-12周静脉给药Ang-(1-7)或Ang-(2-10) （100-400 ng/kg/min）在疾病早期或晚期减轻单肾切除的小鹿头高血压大鼠肾小球损伤的能力。给药大鼠出现高血压和局灶节段性肾小球硬化病变。无论肽剂量或疾病分期如何，通过24小时尿蛋白排泄或肾小球硬化组织学检查，均未观察到Ang-(1-7)或Ang-(2-10)给药后肾小球损伤的减轻。相反，当剂量为400 ng/kg/min时，两种肽均诱导收缩压进一步升高。在牺牲时收获的肾脏中，通过平行反应监测来测量Ang肽的含量。外源性给药Ang-(1-7)和Ang-(2-10)没有导致其相应的肾内水平显著升高。然而，Ang-(1-7)处理的大鼠肾脏匀浆中Ang-(1-7)相对于Ang- ii的相对丰度增加。我们得出结论，在局灶节段性肾小球硬化大鼠模型中，长期静脉注射Ang-(1-7)或Ang-(2-10)并不能改善肾小球损伤，并可能导致血压进一步升高，潜在地加重肾小球损伤。
Unopposed angiotensin (Ang) II-mediated cellular effects may lead to progressive glomerulosclerosis. While Ang-II can be locally generated in the kidneys, we previously showed that glomerular podocytes primarily convert Ang-I, the precursor of Ang-II, to Ang-(1-7) and Ang-(2-10), peptides that have been independently implicated in biological actions opposing those of Ang-II. Therefore, we hypothesized that Ang-(1-7) and Ang-(2-10) could be renoprotective in the fawn-hooded hypertensive rat, a model of focal segmental glomerulosclerosis. We evaluated the ability of 8–12 week-long intravenous administration of either Ang-(1-7) or Ang-(2-10) (100–400 ng/kg/min) to reduce glomerular injury in uni-nephrectomized fawn-hooded hypertensive rats, early or late in the disease. Vehicle-treated rats developed hypertension and lesions of focal segmental glomerulosclerosis. No reduction in glomerular damage was observed, as measured by either 24-hour urinary protein excretion or histological examination of glomerulosclerosis, upon Ang-(1-7) or Ang-(2-10) administration, regardless of peptide dose or disease stage. On the contrary, when given at 400 ng/kg/min, both peptides induced a further increase in systolic blood pressure. Content of Ang peptides was measured by parallel reaction monitoring in kidneys harvested at sacrifice. Exogenous administration of Ang-(1-7) and Ang-(2-10) did not lead to a significant increase in their corresponding intrarenal levels. However, the relative abundance of Ang-(1-7) with respect to Ang-II was increased in kidney homogenates of Ang-(1-7)-treated rats. We conclude that chronic intravenous administration of Ang-(1-7) or Ang-(2-10) does not ameliorate glomerular damage in a rat model of focal segmental glomerulosclerosis and may induce a further rise in blood pressure, potentially aggravating glomerular injury.
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