Targeting methylglyoxal in diabetic kidney disease using the novel mitochondria-targeted compound MitoGamide
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ABSTRACT:
PROVIDER: PRJNA670716 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR12880000.fastq.gz | Fastqsanger.gz | |||
| SRR12880001.fastq.gz | Fastqsanger.gz | |||
| SRR12880002.fastq.gz | Fastqsanger.gz | |||
| SRR12880003.fastq.gz | Fastqsanger.gz | |||
| SRR12880004.fastq.gz | Fastqsanger.gz |
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Project description:Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. Currently there is no treatment to cure diabetes or deal effectively with its complications. In experimental diabetes, mitochondrial dysfunction in the kidney has been widely reported with changes in mitochondrial bioenergetics preceding the development of the renal lesion. Glucose-derived molecules generated during diabetes, known as dicarbonyls, such as methylglyoxal, are thought to impair mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, the novel 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 (10mg/kg/day) or vehicle by oral gavage for 16 weeks. MitoGamide did not alter 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 signalling, 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.
2020-10-23 | GSE159882 | GEO
Project description: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.
| S-EPMC8145135 | biostudies-literature
Project description:PurposeMethylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy.MethodsMale 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks. Several morphological and systemic parameters were assessed, as well as cardiac function by echocardiography.ResultsAkita mice were smaller in size than wild type counterparts in terms of body weight and tibial length. Akita mice exhibited elevated blood glucose and glycated haemoglobin. Total heart and individual ventricles were all smaller in Akita mice. None of the aforementioned parameters was impacted by MitoGamide treatment. Echocardiographic analysis confirmed that cardiac dimensions were smaller in Akita hearts. Diastolic dysfunction was evident in Akita mice, and notably, MitoGamide treatment preferentially improved several of these markers, including e'/a' ratio and E/e' ratio.ConclusionsOur findings suggest that MitoGamide, a novel mitochondria-targeted approach, offers cardioprotection in experimental diabetes and therefore may offer therapeutic potential for the treatment of cardiomyopathy in patients with diabetes.
| S-EPMC6994445 | biostudies-literature
Project description:In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in an experimental model of metabolic syndrome. Dicarbonyl stress was induced in experimental group by intragastrical administration of methylglyoxal (3x/ week in dose 0.5 mg/kg b.wt.for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats (HHTg). Transcriptome assessment in kidney cortex was performed in 8 male adult rats of experimental group and compared to that of 6 age- and sex- matched rats of control group.
2020-02-08 | E-MTAB-7690 | biostudies-arrayexpress
Project description:Diabetic nephropathy is associated with endothelial dysfunction and oxidative stress, in which nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway is impaired. We hypothesize that sGC stimulator, Compound 1, can enhance NO signaling, reduce proteinuria in diabetic nephropathy pre-clinical model with diminished NO-bioavailability and increased oxidized sGC. We therefore, evaluated the effect of sGC stimulator Compound 1 on renal effect in obese ZSF1 rats. Materials and Methods: The sGC stimulator Compound 1, the standard of care agent enalapril, and combination of Compound 1 with enalapril was administered chronically to ZSF1 rats for 6 months. Mean arterial pressure, heart rate, creatinine clearance for estimate glomerular filtration rate (eGFR), urinary protein excretion to creatinine ratio (UPCR), and urinary albumin excretion ratio (UACR) were determined during the study. Histopathology of glomerular and interstitial lesions were assessed at the completion of the study. Results: While both Compound 1 and Enalapril significantly reduced blood pressure the combination of Compound 1 and enalapril normalized blood pressure level. Compound 1 improved eGFR and reduced UPCR and UACR. Combination of enalapril and Compound 1 resulted in marked reduction in UPCR and UACR and improved GFR. Conclusion: The sGC stimulator Compound 1 as a monotherapy slowed renal disease progression and the combination of sGC stimulator with enalapril provided a greater renal protection in a rodent model of diabetic nephropathy.
2021-08-02 | GSE179405 | GEO
Project description:Gene expression in kidney cortex of diabetic mice and menopausal diabetic mice following 6 weeks of diabetes. Diabetes was induced with low-dose streptozotocin injections and menopause was induced by injection of 4-vinylcyclohexene diepoxide. Samples = 12
2010-09-14 | E-GEOD-20702 | biostudies-arrayexpress
Project description:Atherosclerosis-predominant vasculopathy is a common complication of diabetes with high morbidity and high mortality, which is ruining the patient's daily life. As is known to all, traditional Chinese medicine (TCM) SHENQI compound and western medicine rosiglitazone play an important role in the treatment of diabetes. In particular, SHENQI compound has a significant inhibitory effect on vascular lesions. Here, to explore and compare the therapeutic mechanism of SHENQI compound and rosiglitazone on diabetic vasculopathy, we first built 7 groups of mouse models. The behavioral, physiological and pathological morphological characteristics of these mice showed that SHENQI compound has a more comprehensive curative effect than rosiglitazone and has a stronger inhibitory effect on vascular lesions. While rosiglitazone has a more effective but no significant effect on hypoglycemic. Further, based on the gene expression of mice in each group, we performed differential expression analysis. The functional enrichment analysis of these differentially expressed genes (DEGs) revealed the potential pathogenesis and treatment mechanisms of diabetic angiopathy. In addition, we found that SHENQI compound mainly exerts comprehensive effects by regulating MCM8, IRF7, CDK7, NEDD4L by pivot regulator analysis, while rosiglitazone can rapidly lower blood glucose levels by targeting PSMD3, UBA52. Except that, we also identified some pivot TFs and ncRNAs for these potential disease-causing DEG modules, which may the mediators bridging drugs and modules. Finally, similar to pivot regulator analysis, we also identified the regulation of some drugs (e.g. bumetanide, disopyramide and glyburide etc.) which have been shown to have a certain effect on diabetes or diabetic angiopathy, proofing the scientific and objectivity of this study. Overall, this study not only provides an in-depth comparison of the efficacy of SHENQI compound and rosiglitazone in the treatment of diabetic vasculopathy, but also provides clinicians and drug designers with valuable theoretical guidance.
2018-10-19 | GSE121487 | GEO
Project description:Gene expression in kidney cortex of diabetic mice and menopausal diabetic mice following 6 weeks of diabetes. Diabetes was induced with low-dose streptozotocin injections and menopause was induced by injection of 4-vinylcyclohexene diepoxide.
2010-09-14 | GSE20702 | GEO
Project description:The bioactive lipid intermediate palmitoyl CoA (PCoA) can inhibit mitochondrial ADP/ATP transport, though the physiological relevance of this regulation remains unclear. We questioned whether myocardial ischaemia was a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial. Secondly, whether the chronically elevated lipid content within the diabetic heart would make the mitochondria less sensitive to the inhibitory effects of PCoA, with detrimental consequences during ischaemia. Palmitoyl CoA acutely decreased ADP-stimulated state 3 respiration, increasing the Km for ADP 2-fold. The half maximal inhibitory concentration (IC50) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in the diabetic mitochondria, with no significant difference in the Km in the presence of PCoA, and the IC50 increased to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischaemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, to regenerate the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischaemia. However, this beneficial effect was blunted in the diabetic mitochondria. Finally, using 31P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischaemia, with a 3-fold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischaemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism during myocardial ischaemia.
2022-02-17 | PXD024500 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE30528: Transcriptome Analysis of Human Diabetic Kidney Disease (DKD Glomeruli vs. Control Glomeruli) GSE30529: Transcriptome Analysis of Human Diabetic Kidney Disease (DKD Tubuli vs. Control Tubuli) GSE30566: Transcriptome Analysis of Human Diabetic Kidney Disease (Control Glomeruli vs. Control Tubuli) Refer to individual Series
2011-08-02 | E-GEOD-30122 | biostudies-arrayexpress