title: Antioxidant treatment attenuates lactate production in diabetic nephropathy.
abstract: The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-13C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned13C/1H-volume rat coil. The rats received intravenous hyperpolarized [1-13C]pyruvate and were imaged using a slice-selective13C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [13C]alanine levels, indicating an intact glucose-alanine cycle, or [13C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.
authors.affiliation: MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; cl@clin.au.dk.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Laustsen
authors.affiliation: MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Per Mose
authors.identifier: 0000-0001-9767-1852
authors.initials: PM
authors.lastname: Nielsen
authors.affiliation: MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Thomas Stokholm
authors.initials: TS
authors.lastname: Nørlinger
authors.affiliation: MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Qi
authors.affiliation: MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Uffe Kjærgaard
authors.initials: UK
authors.lastname: Pedersen
authors.affiliation: MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Lotte Bonde
authors.initials: LB
authors.lastname: Bertelsen
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Danish Diabetes Academy, Odense, Denmark.
authors.forename: Jakob Appel
authors.initials: JA
authors.lastname: Østergaard
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Flyvbjerg
authors.affiliation: GE Healthcare, Copenhagen, Denmark; and.|Department of Electrical Engineering, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: Jan Henrik
authors.initials: JH
authors.lastname: Ardenkjær-Larsen
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.|Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.|Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
authors.affiliation: MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Stødkilde-Jørgensen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D019344:Lactic Acid / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D013311:Streptozocin
chemical_list: D000975:Antioxidants; D019344:Lactic Acid; D013311:Streptozocin
keywords: MRI; TEMPOL; diabetic nephropathy; hyperpolarization; renal metabolism