Cyclosporin a induces renal episodic hypoxia
Cyclosporin a induces renal episodic hypoxia
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DOI：
10.1111/apha.12811
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发表时间：
2017-03-01
影响因子：
6.3
通讯作者：
Rosenberger, C.
中科院分区：
文献类型：
--
作者：
Fahling, M.;Mathia, S.;Rosenberger, C.
目的：环孢素A （CsA）引起肾毒性。潜在的机制尚不完全清楚，但可能涉及肾脏缺氧和缺氧诱导因子（hfs）。我们在csa诱导的小鼠肾脏中寻找缺氧和Hif，评估它们的时间过程、Hif介导的反应和介入性Hif上调的影响。方法：小鼠注射CsA或其溶剂增热剂6周。低盐饮食（Na+向下箭头）联合CsA增强毒性。我们评估了室内空气下的精细形态学、肾功能、血氧水平依赖的磁共振成像，以及与血管反应性、吡莫硝唑加合物（表明O-2张力低于10 mmHg）、Hif- α蛋白以及Hif靶基因表达相关的呼吸气体成分的变化。通过诱导、基于pax8 - rta的敲除von Hippel-Lindau蛋白（Vhl-KO）实现了稳定的Hif上调，Vhl-KO是Hif-a降解的关键。结果：环孢素A可瞬间升高肾脱氧血红蛋白（R2*）。CsA治疗后2小时血管反应性增强，24小时血管反应性减弱。Na+下行箭头/CsA引起慢性肾衰竭伴肾小管变性和间质纤维化。有损伤风险的肾单元段积累了吡莫硝唑加合物，以及Hif-a蛋白。值得注意的是，Hif靶基因表达保持不变，而因子抑制Hif （Fih）增强。Na+向下箭头/CsA/Vhl-KO加重慢性肾CsA毒性的形态功能结局。结论：环孢素A可引起慢性CsA毒性最敏感的肾细胞段的偶发性缺氧。Fih被上调，并可能阻止进一步的Hif活性。通过Vhl-KO持续的小管Hif上调会恶化慢性csa引起的肾毒性。
Aim: Cyclosporin A (CsA) causes renal toxicity. The underlying mechanisms are incompletely understood, but may involve renal hypoxia and hypoxia-inducible factors (Hifs). We sought for hypoxia and Hif in mouse kidneys with CsA-induced toxicity, assessed their time course, Hifmediated responses and the impact of interventional Hif upregulation.Methods: Mice received CsA or its solvent cremophore for up to 6 weeks. Low salt diet (Na+down arrow)was given in combination with CsA to enhance toxicity. We assessed fine morphology, renal function, blood oxygen leveldependent magnetic resonance imaging under room air and following changes in breathing gas composition which correlate with vascular reactivity, pimonidazole adducts (which indicate O-2 tensions below 10 mmHg), Hif-alpha proteins, as well as expression of Hif target genes. Stable Hif upregulation was achieved by inducible, Pax8-rtTA-based knockout of von Hippel-Lindau protein (Vhl-KO), which is crucial for Hif-a degradation.Results: Cyclosporin A transiently increased renal deoxyhaemoglobin (R2*). Augmented vascular reactivity was observed at 2 h, but decreased at 24 h after CsA treatment. Na+down arrow/CsA provoked chronic renal failure with tubular degeneration and interstitial fibrosis. Nephron segments at risk for injury accumulated pimonidazole adducts, as well as Hif-a proteins. Remarkably, Hif target gene expression remained unchanged, while factor-inhibiting Hif (Fih) was enhanced. Na+down arrow/CsA/Vhl-KO aggravated morpho-functional outcome of chronic renal CsA toxicity.Conclusions: Cyclosporin A provokes episodic hypoxia in nephron segments most susceptible to chronic CsA toxicity. Fih is upregulated and likely blocks further Hif activity. Continuous tubular Hif upregulation via Vhl-KO worsens the outcome of chronic CsA-induced renal toxicity.