Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide.

Sih Min Tan,Adrienne Laskowski,Richard C Hartley,Michael P Murphy,Thomas Krieg,Carlos D Baeza-Garza,Mark E Cooper,Cesare Granata,Runa S J Lindblom,Mark Ziemann,Melinda T Coughlan,Vicki Thallas-Bonke,Stuart T Caldwell,Matthew Snelson,Assam El-Osta

doi:10.3390/nu13051457

Abstract

Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.

Highlights

Introduction conditions of the Creative CommonsChronic kidney disease (CKD) impacts more than 50 million individuals globally [1]and is a key risk factor for cardiovascular disease and all-cause mortality [2]
MitoGamide was detected in the heart, kidney, and liver in mice 1 h after oral gavage (Figure S1)
We have previously shown that at 26 weeks of age, Akita mice display increased in albuminuria, glomerulosclerosis, and oxidative stress, which features a reminiscent of human Diabetic kidney disease (DKD) [48]

Summary

Introduction

Introduction conditions of the Creative CommonsChronic kidney disease (CKD) impacts more than 50 million individuals globally [1]and is a key risk factor for cardiovascular disease and all-cause mortality [2]. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-hyperglycemic medications that are approved and indicated for type 2 diabetes and have shown promising renoprotective effects independent of their glucose lowering actions [5]. Their use in type 1 diabetes is limited, mainly due to complications such as diabetic ketoacidosis as the main safety concern [6]. There is a critical need to identify pathogenic factors responsible for the onset and progression of DKD especially in type 1 diabetes in order to develop new therapeutic targets. Changes in the regulation of mitochondrial dynamics and bioenergetics are present prior to the development of early renal structural and biochemical lesions in diabetes [19]

Methods

Results

Conclusion