High Intrarenal Lactate Production Inhibits the Renal Pseudohypoxic Response to Acutely Induced Hypoxia in Diabetes.

Christoffer Laustsen,Fredrik Palm,Jan Henrik Ardenkjær-Larsen,Jakob Appel Østergaard,Lotte Bonde Bertelsen,Per Mose Nielsen,Allan Flyvbjerg,Michael Pedersen,Kasper Lipsø

doi:10.18383/j.tom.2019.00003

Abstract

Intrarenal hypoxia develops within a few days after the onset of insulinopenic diabetes in an experimental animal model (ie, a model of type-1 diabetes). Although diabetes-induced hypoxia results in increased renal lactate formation, mitochondrial function is well maintained, a condition commonly referred to as pseudohypoxia. However, the metabolic effects of significantly elevated lactate levels remain unclear. We therefore investigated in diabetic animals the response to acute intrarenal hypoxia in the presence of high renal lactate formation to delineate mechanistic pathways and compare these findings to healthy control animals. Hyperpolarized 13C-MRI and blood oxygenation level–dependent 1H-MRI was used to investigate the renal metabolism of [1-13C]pyruvate and oxygenation following acutely altered oxygen content in the breathing gas in a streptozotocin rat model of type-1 diabetes with and without insulin treatment and compared with healthy control rats. The lactate signal in the diabetic kidney was reduced by 12%–16% during hypoxia in diabetic rats irrespective of insulin supplementation. In contrast, healthy controls displayed the well-known Pasteur effect manifested as a 10% increased lactate signal following reduction of oxygen in the inspired air. Reduced expression of the monocarboxyl transporter-4 may account for altered response to hypoxia in diabetes with a high intrarenal pyruvate-to-lactate conversion. Reduced intrarenal lactate formation in response to hypoxia in diabetes shows the existence of a different metabolic phenotype, which is independent of insulin, as insulin supplementation was unable to affect the pyruvate-to-lactate conversion in the diabetic kidney.

Highlights

In the diabetic kidney, hyperglycemia activates primarily mitochondrial uncoupling and secondarily the production of reactive oxygen species, which reduces energy production and creates hypoxia and an increased oxygen sensitivity in the kidney [1,2,3,4,5]
Renal oxygen availability depended on the inspired oxygen content, and blood oxygenation level– dependent (BOLD) Magnetic resonance imaging (MRI) showed a significantly decreased T2* in the renal cortex in all groups following a reduction in the oxygen content of the breathing gas (P Ͻ .001) (Figure 2)
The pyruvate-to-total carbon ratio increased after administration of a low oxygen content in the diabetes group compared with controls (P Ͻ .001), and similar findings were found in the diabetes ϩ insulin group (P Ͻ .001), while a tendency toward a decreased pyruvate signal was observed in the diabetes ϩ insulin group (P ϭ .070) (Figure 3)

Summary

Introduction

Hyperglycemia activates primarily mitochondrial uncoupling and secondarily the production of reactive oxygen species, which reduces energy production and creates hypoxia and an increased oxygen sensitivity in the kidney [1,2,3,4,5]. Important to assess the metabolic balance (PDH versus LDH) are the blood oxygenation level– dependent (BOLD) method and the metabolic imaging approach referred to as hyperpolarized 13C-based magnetic resonance (MR) spectroscopy [5, 16,17,18,19]. The combination of these 2 methods enables longitudinal assessment of oxygen availability in parallel with PDH ([1-13C]pyruvate-to-13C-bicarbonate conversion) and LDH ([1-13C]pyruvate-to-[1-13C]lactate conversion) flux estimation directly in the kidney tissue in vivo [5].

Methods

Results

Conclusion