1. Cyclosporin a induces renal episodic hypoxia.
- Author
-
Fähling, M., Mathia, S., Scheidl, J., Abramovitch, R., Milman, Z., Paliege, A., Peters, H., Persson, P. B., Heyman, S. N., and Rosenberger, C.
- Subjects
CYCLOSPORINE ,HYPOXIA-inducible factors ,KIDNEY physiology ,NEPHROTOXICOLOGY ,KIDNEYS ,MAGNETIC resonance imaging - Abstract
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, Hif-mediated 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
+ ↓) 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 O2 tensions below 10 mmHg), Hif- α proteins, as well as expression of Hif target genes. Stable Hif upregulation was achieved by inducible, Pax8-rt TA-based knockout of von Hippel-Lindau protein (Vhl- KO), which is crucial for Hif- α 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+ ↓/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. 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. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF