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Protective role of PGC-1? in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling.

ABSTRACT: The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1? in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1?-overexpressing plasmid (pcDNA3-PGC-1?) for 48 h. In the diabetic rats, decreased PGC-1? expression was associated with increased mitochondrial ROS generation in the renal cortex, increased proteinuria, glomerular hypertrophy, and higher glomerular 8-OHdG (a biomarker for oxidative stress). In vitro, hyperglycemia induced the downregulation of PGC-1?, which led to increased DRP1 expression, increased mitochondrial fragmentation and damaged network structure. This was associated with an increase in ROS generation and mesangial cell hypertrophy. These pathological changes were reversed in vitro by the transfection of pcDNA3-PGC-1?. These data suggest that PGC-1? may protect DN via the inhibition of DRP1-mediated mitochondrial dynamic remodeling and ROS production. These findings may assist the development of novel therapeutic strategies for patients with DN.

SUBMITTER: Guo K

PROVIDER: S-EPMC4390193 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling.

Guo Kaifeng K Lu Junxi J Huang Yan Y Wu Mian M Zhang Lei L Yu Haoyong H Zhang Mingliang M Bao Yuqian Y He John Cijiang JC Chen Haibing H Jia Weiping W

PloS one 20150408 4

The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1α-overexpressing plasmid (pcDNA3-PGC-1α) for 48 h. In the diabetic rats, decreased PGC-1α expression was associated with i ...[more]

PMID: 25853493

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging.MethodsWestern blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed.ResultsThe Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α.ConclusionsThese results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

Dataset Information

Protective role of PGC-1? in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling.

Publications

Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling.

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