Article

TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis.

Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 01/2009; 379(1):43-8. DOI: 10.1016/j.bbrc.2008.11.141
Source: PubMed

ABSTRACT Although it has been reported that thiazolidinediones (TZDs) may reduce cardiovascular events in type 2 diabetic patients, its precise mechanism is unclear. We previously demonstrated that hyperglycemia-induced production of reactive oxygen species from mitochondria (mtROS) contributed to the development of diabetic complications, and metformin normalized mt ROS production by induction of MnSOD and promotion of mitochondrial biogenesis by activating the PGC-1alpha pathway. In this study, we examined whether TZDs could inhibit hyperglycemia-induced mtROS production by activating the PGC-1alpha pathway. We revealed that pioglitazone and ciglitazone attenuated hyperglycemia-induced ROS production in human umbilical vein endothelial cells (HUVECs). Both TZDs increased the expression of NRF-1, TFAM and MnSOD mRNA. Moreover, pioglitazone increased mtDNA and mitochondrial density. These results suggest that TZDs normalize hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis by activating PGC-1alpha. This phenomenon could contribute to the prevention of diabetic vascular complications.

0 Bookmarks
 · 
132 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mechanism(s) underlying renoprotection by peroxisome proliferator-activated receptor-gamma (PPARγ) agonists in diabetic and non-diabetic kidney disease are not well-understood. Mitochondrial dysfunction and oxidative stress contribute to kidney disease. PPARγ upregulates proteins required for mitochondrial biogenesis. Our aim was to determine whether PPARγ has a role in protecting kidney proximal tubular epithelium (PTE) against mitochondrial destabilisation and oxidative stress. HK-2 PTE cells were subjected to oxidative stress (0.2-1.0mM hydrogen peroxide/H2O2) for 2h and 18h and compared with untreated cells for: apoptosis, mitosis (morphology/biomarkers); cell viability (MTT); superoxide (dihydroethidium/DHE); mitochondrial function (MitoTracker Red; JC-1); ATP (luminescence); and mitochondrial ultrastructure. PPARγ, phospho-PPARγ, PPARγ-coactivator-1α (PGC-1α), Parkin (Park2), p62 and light chain3-beta (LC3β) were investigated using Western blots. PPARγ was modulated using the agonists rosiglitazone, pioglitazone and troglitazone. Mitochondrial destabilisation increased with H2O2 concentration: ATP decreased (2h, 18h; p<0.05); Mitotracker Red and JC-1 fluorescence indicated loss of mitochondrial membrane potential; and superoxide increased (18h; p<0.05). Electron microscopy indicated sparse mitochondria, with disrupted cristae. Mitophagy was evident at 2h (Park2, LC3β increased; p62 decreased). Impaired mitophagy was indicated by p62 accumulation at 18h (p<0.05). PPARγ expression decreased, phospho-PPARγ increased and PGC-1α decreased (2h), indicating aberrant PPARγ activation and reduced mitochondrial biogenesis. Cell viability decreased (2h & 18h; p<0.05). PPARγ agonists promoted further apoptosis. In summary, oxidative stress promoted mitochondrial destabilisation in kidney PTE, in association with increased PPARγ phosphorylation. PPARγ agonists failed to protect PTE. Despite positive effects in other tissues, PPARγ activation appears to be detrimental to kidney PTE health when oxidative stress induces damage.
    American journal of physiology. Renal physiology 08/2014; · 3.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes is considered a major risk factor for stroke and is associated with worsened stroke outcomes. Here, we discuss and summarize the mechanisms that have been associated with the increased risk of stroke due to the hyperglycemia in diabetes mellitus. In diabetic stroke models, hyperglycemia exaggerates the following damaging processes: acidosis, accumulation of reactive oxygen species/reactive nitrogen, inflammation and mitochondrial dysfunction. Understanding the mechanism of diabetes acting as a stroke risk factor will definitely assist to reveal issues related to drug metabolism and toxicity in diabetic stroke. In addition, it is suggested that future studies may focus on the mechanisms mediating blood-brain barrier and astrocytes dysfunction under hyperglycemic stroke.
    Journal of drug metabolism & toxicology. 06/2013; 4(4).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria are perhaps the most sophisticated and dynamic responsive sensing systems in eukaryotic cells. The role of mitochondria goes beyond their capacity to create molecular fuel and includes the generation of reactive oxygen species, the regulation of calcium, and the activation of cell death. In endothelial cells, mitochondria have a profound impact on cellular function under both healthy and diseased conditions. In this review, we summarize the basic functions of mitochondria in endothelial cells and discuss the roles of mitochondria in endothelial dysfunction and vascular diseases, including atherosclerosis, diabetic vascular dysfunction, pulmonary artery hypertension, and hypertension. Finally, the potential therapeutic strategies to improve mitochondrial function in endothelial cells and vascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants and calorie restriction.
    Frontiers in Physiology 05/2014; 5:175.