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

Guo K, Lu J, Huang Y, Wu M, Zhang L, Yu H, Zhang M, Bao Y, He JC, Chen H, Jia W - PLoS ONE (2015)

Bottom Line: This was associated with an increase in ROS generation and mesangial cell hypertrophy.These data suggest that PGC-1α 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

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-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 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-1α, 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-1α. These data suggest that PGC-1α 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.

No MeSH data available.


Related in: MedlinePlus

PGC-1α suppresses mesangial cell hypertrophy induced by hyperglycemia.The ratio of total amount of protein to cell number (A) and cell morphology (B) in RMCs incubated in normal glucose (NG) and high glucose (HG) conditions, RMCs transfected with PGC-1α shRNA or shRNA-con under NG conditions (NG+PGC-1α shRNA, NG+shRNA-con), and RMCs transfected with pcDNA3-PGC-1α or pcDNA3 under to HG conditions (HG+pcDNA3-PGC-1α, HG+pcDNA3). Data are represented as the mean ± SD values from three cells per group, and the experiments were repeated independently at least three times (*P < 0.05 vs. NG, ## P < 0.01 vs. HG). Scale bar: 10 μm.
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pone.0125176.g005: PGC-1α suppresses mesangial cell hypertrophy induced by hyperglycemia.The ratio of total amount of protein to cell number (A) and cell morphology (B) in RMCs incubated in normal glucose (NG) and high glucose (HG) conditions, RMCs transfected with PGC-1α shRNA or shRNA-con under NG conditions (NG+PGC-1α shRNA, NG+shRNA-con), and RMCs transfected with pcDNA3-PGC-1α or pcDNA3 under to HG conditions (HG+pcDNA3-PGC-1α, HG+pcDNA3). Data are represented as the mean ± SD values from three cells per group, and the experiments were repeated independently at least three times (*P < 0.05 vs. NG, ## P < 0.01 vs. HG). Scale bar: 10 μm.

Mentions: The earliest morphological change in DN is mesangial cell hypertrophy, which results from an increase in protein synthesis in the absence of an increase in DNA synthesis. As shown in Fig 5, the ratio of the amount of total protein to cell number and cell morphology in RMCs with and without pcDNA3 plasmid transfection under HG conditions or in RMCs transfected with PGC-1α shRNA under NG conditions were significantly greater than NG group (P < 0.05); there were no significant differences between the NG group and the shRNA-con group (Fig 5). Moreover, we found that RMC hypertrophy promoted by hyperglycemia was ameliorated in RMCs that expressed exogenous PGC-1α (Fig 5).


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

Guo K, Lu J, Huang Y, Wu M, Zhang L, Yu H, Zhang M, Bao Y, He JC, Chen H, Jia W - PLoS ONE (2015)

PGC-1α suppresses mesangial cell hypertrophy induced by hyperglycemia.The ratio of total amount of protein to cell number (A) and cell morphology (B) in RMCs incubated in normal glucose (NG) and high glucose (HG) conditions, RMCs transfected with PGC-1α shRNA or shRNA-con under NG conditions (NG+PGC-1α shRNA, NG+shRNA-con), and RMCs transfected with pcDNA3-PGC-1α or pcDNA3 under to HG conditions (HG+pcDNA3-PGC-1α, HG+pcDNA3). Data are represented as the mean ± SD values from three cells per group, and the experiments were repeated independently at least three times (*P < 0.05 vs. NG, ## P < 0.01 vs. HG). Scale bar: 10 μm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4390193&req=5

pone.0125176.g005: PGC-1α suppresses mesangial cell hypertrophy induced by hyperglycemia.The ratio of total amount of protein to cell number (A) and cell morphology (B) in RMCs incubated in normal glucose (NG) and high glucose (HG) conditions, RMCs transfected with PGC-1α shRNA or shRNA-con under NG conditions (NG+PGC-1α shRNA, NG+shRNA-con), and RMCs transfected with pcDNA3-PGC-1α or pcDNA3 under to HG conditions (HG+pcDNA3-PGC-1α, HG+pcDNA3). Data are represented as the mean ± SD values from three cells per group, and the experiments were repeated independently at least three times (*P < 0.05 vs. NG, ## P < 0.01 vs. HG). Scale bar: 10 μm.
Mentions: The earliest morphological change in DN is mesangial cell hypertrophy, which results from an increase in protein synthesis in the absence of an increase in DNA synthesis. As shown in Fig 5, the ratio of the amount of total protein to cell number and cell morphology in RMCs with and without pcDNA3 plasmid transfection under HG conditions or in RMCs transfected with PGC-1α shRNA under NG conditions were significantly greater than NG group (P < 0.05); there were no significant differences between the NG group and the shRNA-con group (Fig 5). Moreover, we found that RMC hypertrophy promoted by hyperglycemia was ameliorated in RMCs that expressed exogenous PGC-1α (Fig 5).

Bottom Line: This was associated with an increase in ROS generation and mesangial cell hypertrophy.These data suggest that PGC-1α 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

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-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 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-1α, 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-1α. These data suggest that PGC-1α 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.

No MeSH data available.


Related in: MedlinePlus