1. ¹Nephrology and Medical Intensive Care, Charité University Clinic, Berlin, Germany
2. ²Departments of Medicine, Hadassah Hospitals, Mt Scopus and Ein Kerem and the Hebrew University Medical School, Jerusalem, Israel
3. ³Diabetes Research Unit, Hadassah Hospital, Ein Kerem and the Hebrew University Medical School, Jerusalem, Israel
4. ⁴Department of Physiology, Technion Medical School, Haifa, Israel
5. ⁵Nephrology Unit, Bikur Holim Hospital, Jerusalem, Israel
6. ⁶Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany
7. ⁷Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

Correspondence: C Rosenberger, Nephrology and Medical Intensive Care, Charité Universitaetsmedizin, Augustenburger Platz 1, Berlin 13353, Germany. E-mail: chrosenbe@aol.com

Received 2 February 2007; Revised 6 July 2007; Accepted 7 August 2007; Published online 3 October 2007.

Abstract

Hypoxia of the kidney in diabetes could predispose it to develop acute and chronic renal failure. To examine the relationship between renal hypoxia and renal failure, we measured hypoxia (as a pimonidazole adducts), hypoxia-inducible factors (HIFs), and a hypoxia target gene heme oxygenase-1. The studies were performed in rats with streptozotocin (STZ)-induced diabetes, Cohen diabetes sensitive rats, and during short-term artificial hyperglycemia in rats induced by intravenous glucose and octreotide. STZ-treated rats received insulin, the superoxide dismutase mimetic tempol, or contrast medium. Radiocontrast media causes hypoxia and HIF induction. Hypoxia, HIFs, and heme oxygenase were undetectable in controls, but transiently activated in STZ-treated and the Cohen diabetes sensitive rats. Different patterns of HIFs and pimonidazole were observed between the three models. Insulin abolished pimonidazole and HIF induction, whereas tempol lead to increased HIFs and heme oxygenase induction at similar levels of pimonidazole. When compared with control rats, STZ-treated rats exhibited more intense and protracted renal pimonidazole, with augmented hypoxia inducible factor production and reduced GFR following contrast media. Our data suggest that both regional hypoxia and hypoxia adaptation transiently occur in early stages of experimental diabetes, largely dependent on hyperglycemia or after contrast media. Tempol may augment the HIF response in diabetes.