Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide
| Autor: | Richard C. Hartley, Michael P. Murphy, Runa S.J. Lindblom, Sih Min Tan, Assam El-Osta, Thomas Krieg, Cesare Granata, Mark Ziemann, Stuart T. Caldwell, Melinda T. Coughlan, Mark E. Cooper, Vicki Thallas-Bonke, Carlos D. Baeza-Garza, Adrienne Laskowski, Matthew Snelson |
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| Přispěvatelé: | Lindblom, Runa SJ [0000-0001-6755-8744], Granata, Cesare [0000-0002-3509-6001], Snelson, Matthew [0000-0003-4829-9550], El-Osta, Assam [0000-0001-7968-7375], Baeza-Garza, Carlos D [0000-0002-7423-4948], Krieg, Thomas [0000-0002-5192-580X], Murphy, Michael P [0000-0003-1115-9618], Coughlan, Melinda T [0000-0001-8846-6443], Apollo - University of Cambridge Repository, Lindblom, Runa S. J. [0000-0001-6755-8744], Baeza-Garza, Carlos D. [0000-0002-7423-4948], Murphy, Michael P. [0000-0003-1115-9618], Coughlan, Melinda T. [0000-0001-8846-6443] |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty kidney 030204 cardiovascular system & hematology Mitochondrion medicine.disease_cause Article Diabetes Mellitus Experimental Diabetes Complications 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Diabetes mellitus Internal medicine medicine Renal fibrosis methylglyoxal Animals TX341-641 Kidney dicarbonyl Nutrition and Dietetics diabetes business.industry Nutrition. Foods and food supply sugar-derived products MitoGamide Methylglyoxal Glomerulosclerosis medicine.disease Pyruvaldehyde Mitochondria Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Benzamides Albuminuria Kidney Diseases medicine.symptom business Oxidative stress Food Science |
| Zdroj: | Nutrients Volume 13 Issue 5 Nutrients, Vol 13, Iss 1457, p 1457 (2021) |
| ISSN: | 2072-6643 |
| DOI: | 10.17863/cam.76508 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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