Cyclosporin a induces renal episodic hypoxia.
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 O2tensions 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.
Vegetative Physiologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.
M
M
Fähling
Vegetative Physiologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Nephrology and Renal Transplantation, Charité - Universitätsmedizin Berlin, Berlin, Germany.
S
S
Mathia
Gastroenterology, Krankenhaus Westend, Berlin, Germany.
J
J
Scheidl
The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
R
R
Abramovitch
The Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Z
Z
Milman
Nephrology and Renal Transplantation, Charité - Universitätsmedizin Berlin, Berlin, Germany.
A
A
Paliege
Nephrology and Renal Transplantation, Charité - Universitätsmedizin Berlin, Berlin, Germany.
H
H
Peters
Vegetative Physiologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.
P B
PB
Persson
Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
S N
SN
Heyman
Nephrology and Renal Transplantation, Charité - Universitätsmedizin Berlin, Berlin, Germany.
C
C
Rosenberger
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects*; D016572:Cyclosporine / Q000633:toxicity*; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000378:metabolism; D015854:Up-Regulation
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D006899:Mixed Function Oxygenases; C551240:factor inhibiting hypoxia-inducible factor 1, mouse
Hif; cyclosporin A; episodic hypoxia; renal fibrosis