Antioxidant treatment attenuates lactate production in diabetic nephropathy

Abstract

The early progression of diabetic nephropathy is notoriously difficult to detect and quantify prior to the occurrence of substantial histological damage. Recently, hyperpolarized [1-13 C] 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 weeks after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned 13 C/ 1 H-volume rat coil. The rats received intravenous hyperpolarized [1-13 C] pyruvate and were imaged using a slice-selective 13 C-IDEAL spiral sequence.Untreated diabetic rats showed increased renal lactate production compared to 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 13 C-alanine levels,indicating an intact glucose-alanine cycle, or 13 C-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 for renal metabolic alterations occurring in early diabetes.4

Fumarase activity: an in vivo and in vitro biomarker for acute kidney injury

“…We have recently demonstrated metabolic alterations in post-ischemic unilateral IRI rats following hyperpolarized [1- 13 C]pyruvate infusion16. Showing an upregulation of the anaerobic pathways, similarly to what has been demonstrated in diabetic kidney171819, albeit lower total turnover, most likely caused by necrosis. In principle any small molecular probe can be hyperpolarized as long as they contain a nuclear spin, typically 13 C2021.…”

Effects of anesthesia on renal function and metabolism in rats assessed by hyperpolarized MRI

“…The rest of the arterial blood was spun for plasma purification in heparin‐coated tubes. Kidney tissue and urine were collected as previously described …”

Glucagon infusion alters the hyperpolarized 13C‐urea renal hemodynamic signature

“…Interestingly, reductions in renal gluconeogenesis have previously been demonstrated to alter renal [1‐ 13 C] lactate accumulation/production following injection of hyperpolarized [1‐ 13 C] pyruvate, in turn supporting the shift in energy production and utilization with altered functional demand (increased lactate accumulation/production with decreasing renal glucose production) . In diabetic animals, exhibition of both increased renal gluconeogenesis and intrarenal lactate production largely shields them from the effects originating from the reduction in gluconeogenesis …”