Fähling M, Mathia S, Scheidl J, Abramovitch R, Milman Z, Paliege A, Peters H, Persson P B, Heyman S N, Rosenberger C
Vegetative Physiologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Nephrology and Renal Transplantation, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Acta Physiol (Oxf). 2017 Mar;219(3):625-639. doi: 10.1111/apha.12811. Epub 2016 Oct 18.
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, Hif-mediated responses and the impact of interventional Hif upregulation.
Mice received CsA or its solvent cremophore for up to 6 weeks. Low salt diet (Na ↓) was given in combination with CsA to enhance toxicity. We assessed fine morphology, renal function, blood oxygen level-dependent magnetic resonance imaging under room air and following changes in breathing gas composition which correlate with vascular reactivity, pimonidazole adducts (which indicate O tensions below 10 mmHg), Hif-α 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-α degradation.
Cyclosporin A transiently increased renal deoxyhaemoglobin (R2*). Augmented vascular reactivity was observed at 2 h, but decreased at 24 h after CsA treatment. Na ↓/CsA provoked chronic renal failure with tubular degeneration and interstitial fibrosis. Nephron segments at risk for injury accumulated pimonidazole adducts, as well as Hif-α proteins. Remarkably, Hif target gene expression remained unchanged, while factor-inhibiting Hif (Fih) was enhanced. Na ↓/CsA/Vhl-KO aggravated morpho-functional outcome of chronic renal CsA toxicity.
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.
环孢素A（CsA）可导致肾毒性。其潜在机制尚未完全明确，但可能涉及肾缺氧及缺氧诱导因子（Hifs）。我们在CsA诱导毒性的小鼠肾脏中探寻缺氧及Hif情况，评估其时间进程、Hif介导的反应以及干预性Hif上调的影响。
小鼠接受CsA或其溶剂聚氧乙烯蓖麻油长达6周。低盐饮食（Na↓）与CsA联合使用以增强毒性。我们评估了精细形态学、肾功能、在室内空气条件下以及呼吸气体成分改变（与血管反应性相关）后的血氧水平依赖磁共振成像、匹莫硝唑加合物（指示氧分压低于10 mmHg）、Hif-α蛋白以及Hif靶基因的表达。通过基于诱导型、Pax8-rtTA的冯·希佩尔-林道蛋白敲除（Vhl-KO）实现稳定的Hif上调，该蛋白对Hif-α降解至关重要。
环孢素A使肾脱氧血红蛋白（R2*）短暂增加。CsA治疗后2小时观察到血管反应性增强，但24小时时降低。Na↓/CsA引发慢性肾衰竭，伴有肾小管变性和间质纤维化。有损伤风险的肾单位节段积累了匹莫硝唑加合物以及Hif-α蛋白。值得注意的是，Hif靶基因表达保持不变，而抑制Hif的因子（Fih）增强。Na↓/CsA/Vhl-KO加重了慢性肾CsA毒性的形态功能结局。
环孢素A在最易受慢性CsA毒性影响的肾单位节段引发间歇性缺氧。Fih上调并可能阻断进一步的Hif活性。通过Vhl-KO持续上调肾小管Hif会使慢性CsA诱导的肾毒性结局恶化。
