Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide.
Sih Min TanRuna S J LindblomMark ZiemannAdrienne LaskowskiCesare GranataMatthew SnelsonVicki Thallas-BonkeAssam El-OstaCarlos D Baeza-GarzaStuart T CaldwellRichard C HartleyThomas KriegMark E CooperMichael P MurphyMelinda T CoughlanPublished in: Nutrients (2021)
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.
Keyphrases
- type diabetes
- body composition
- glycemic control
- blood glucose
- end stage renal disease
- cancer therapy
- cardiovascular disease
- cell death
- chronic kidney disease
- high fat diet induced
- endoplasmic reticulum
- peritoneal dialysis
- oxidative stress
- reactive oxygen species
- resistance training
- stem cells
- clinical trial
- south africa
- wild type
- adipose tissue
- risk assessment
- small molecule
- phase ii
- metabolic syndrome
- mesenchymal stem cells
- placebo controlled
- postmenopausal women
- single cell
- skeletal muscle
- combination therapy
- diabetic rats
- amino acid
- protein protein
- respiratory tract