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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 expression was decreased in the kidney of diabetic rats and correlated with renal lesions.A: Real-time RT-PCR assay for PGC-1α mRNA relative to the control values. B: Western blotting analysis of PGC-1α expression in the control rats (control) and diabetic rats (DM). Equal protein loading was confirmed by staining with the tubulin antibody. C: Result of the correlation analysis between PGC-1α protein expression and 24-h microalbuminuria level. D: Glomerular H&E staining in the control and diabetes groups. Glomerular hypertrophy was obvious in the diabetes group. Original magnification: ×400. E: Immunohistochemical detection of fibronectin (FN) in glomeruli from control and diabetic rats. Data are expressed as the mean ± SD values from 5–10 rats per group, and the experiments were repeated independently at least 3 times with similar results (**P < 0.01 vs. the control; ***P < 0.001 vs. the control). Scale bar: 25 μm.
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pone.0125176.g001: PGC-1α expression was decreased in the kidney of diabetic rats and correlated with renal lesions.A: Real-time RT-PCR assay for PGC-1α mRNA relative to the control values. B: Western blotting analysis of PGC-1α expression in the control rats (control) and diabetic rats (DM). Equal protein loading was confirmed by staining with the tubulin antibody. C: Result of the correlation analysis between PGC-1α protein expression and 24-h microalbuminuria level. D: Glomerular H&E staining in the control and diabetes groups. Glomerular hypertrophy was obvious in the diabetes group. Original magnification: ×400. E: Immunohistochemical detection of fibronectin (FN) in glomeruli from control and diabetic rats. Data are expressed as the mean ± SD values from 5–10 rats per group, and the experiments were repeated independently at least 3 times with similar results (**P < 0.01 vs. the control; ***P < 0.001 vs. the control). Scale bar: 25 μm.

Mentions: The expression of PGC-1α in the renal cortex was significantly decreased in the diabetic rats at the level of both mRNA and protein; moreover, the level of proteinuria was also significantly higher in the diabetic rats compared with the control rats (Fig 1A and 1B and Table 1; P < 0.01). There was significant negative correlation between the expression of PGC-1α and the level of proteinuria (Fig 1C). In addition, pathological changes affecting the kidney were observed in diabetic rats, such as increased kidney/body weight ratio, increased glomerular volume, and increased glomerular fibronectin (FN) levels, which indicated a significant increase in the amount of extracellular matrix (Table 1 and Fig 1D and 1E; P < 0.01). Additionally, the levels of blood glucose, triglyceride, and cholesterol were significantly increased in the diabetic group compared with the control group (Table 1; P < 0.01).


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 expression was decreased in the kidney of diabetic rats and correlated with renal lesions.A: Real-time RT-PCR assay for PGC-1α mRNA relative to the control values. B: Western blotting analysis of PGC-1α expression in the control rats (control) and diabetic rats (DM). Equal protein loading was confirmed by staining with the tubulin antibody. C: Result of the correlation analysis between PGC-1α protein expression and 24-h microalbuminuria level. D: Glomerular H&E staining in the control and diabetes groups. Glomerular hypertrophy was obvious in the diabetes group. Original magnification: ×400. E: Immunohistochemical detection of fibronectin (FN) in glomeruli from control and diabetic rats. Data are expressed as the mean ± SD values from 5–10 rats per group, and the experiments were repeated independently at least 3 times with similar results (**P < 0.01 vs. the control; ***P < 0.001 vs. the control). Scale bar: 25 μm.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0125176.g001: PGC-1α expression was decreased in the kidney of diabetic rats and correlated with renal lesions.A: Real-time RT-PCR assay for PGC-1α mRNA relative to the control values. B: Western blotting analysis of PGC-1α expression in the control rats (control) and diabetic rats (DM). Equal protein loading was confirmed by staining with the tubulin antibody. C: Result of the correlation analysis between PGC-1α protein expression and 24-h microalbuminuria level. D: Glomerular H&E staining in the control and diabetes groups. Glomerular hypertrophy was obvious in the diabetes group. Original magnification: ×400. E: Immunohistochemical detection of fibronectin (FN) in glomeruli from control and diabetic rats. Data are expressed as the mean ± SD values from 5–10 rats per group, and the experiments were repeated independently at least 3 times with similar results (**P < 0.01 vs. the control; ***P < 0.001 vs. the control). Scale bar: 25 μm.
Mentions: The expression of PGC-1α in the renal cortex was significantly decreased in the diabetic rats at the level of both mRNA and protein; moreover, the level of proteinuria was also significantly higher in the diabetic rats compared with the control rats (Fig 1A and 1B and Table 1; P < 0.01). There was significant negative correlation between the expression of PGC-1α and the level of proteinuria (Fig 1C). In addition, pathological changes affecting the kidney were observed in diabetic rats, such as increased kidney/body weight ratio, increased glomerular volume, and increased glomerular fibronectin (FN) levels, which indicated a significant increase in the amount of extracellular matrix (Table 1 and Fig 1D and 1E; P < 0.01). Additionally, the levels of blood glucose, triglyceride, and cholesterol were significantly increased in the diabetic group compared with the control group (Table 1; P < 0.01).

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