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Published on: November 21, 2025
Cyclosporin a induces renal episodic hypoxia
M Fähling1, S Mathia1,2, J Scheidl3
1Vegetative Physiologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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-rtTA-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.
Insights
Cyclosporin A causes kidney damage by inducing temporary hypoxia. Upregulating hypoxia-inducible factors (Hifs) worsens this renal toxicity, suggesting Hifs are not protective in this context.
Area of Science:
- Nephrology
- Molecular Biology
- Biomedical Imaging
Background:
- Cyclosporin A (CsA) is known to cause renal toxicity, but the exact mechanisms remain unclear.
- Renal hypoxia and hypoxia-inducible factors (Hifs) are suspected contributors to CsA-induced kidney damage.
Purpose of the Study:
- To investigate the presence and role of hypoxia and Hifs in mouse kidneys experiencing CsA-induced toxicity.
- To analyze the temporal dynamics of hypoxia and Hif activity.
- To assess the impact of experimentally induced Hif upregulation on CsA nephrotoxicity.
Main Methods:
- Mice were treated with CsA, with or without a low salt diet, for up to six weeks.
- Renal function, morphology, and oxygen levels (using blood oxygen level-dependent MRI and pimonidazole adducts) were assessed.
- Hypoxia-inducible factor alpha (Hif-α) protein levels and target gene expression were analyzed.
- Stable Hif upregulation was achieved by knocking out the von Hippel-Lindau protein (Vhl).
Main Results:
- CsA induced transient renal hypoxia and altered vascular reactivity.
- Combined low salt diet and CsA treatment led to chronic renal failure, tubular damage, and interstitial fibrosis.
- Affected nephron segments showed accumulation of pimonidazole adducts and Hif-α proteins.
- Despite Hif-α accumulation, Hif target gene expression was unchanged, but factor-inhibiting Hif (Fih) was upregulated.
- Interventionally upregulated Hif (via Vhl-KO) worsened the morpho-functional outcomes of chronic CsA toxicity.
Conclusions:
- Cyclosporin A triggers episodic hypoxia in susceptible nephron segments, contributing to chronic kidney damage.
- Enhanced factor-inhibiting Hif (Fih) likely limits the cellular response to hypoxia.
- Sustained upregulation of Hifs through Vhl knockout exacerbates CsA-induced renal toxicity, indicating a detrimental role in this context.
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