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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Hydroxy-2'-Deoxyguanosine
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Animals
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Biomarkers / metabolism
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Deoxyguanosine / analogs & derivatives
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Deoxyguanosine / metabolism
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Diabetic Nephropathies / genetics
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Diabetic Nephropathies / metabolism*
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Diabetic Nephropathies / pathology
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Dynamins / genetics*
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Dynamins / metabolism
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Gene Expression Regulation
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Glucose / metabolism
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Glucose / pharmacology
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Humans
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Hyperglycemia / genetics
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Hyperglycemia / metabolism*
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Hyperglycemia / pathology
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Male
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Mesangial Cells / drug effects
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Mesangial Cells / metabolism
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Mesangial Cells / pathology
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / pathology
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Mitochondrial Dynamics / drug effects
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Mitochondrial Dynamics / genetics*
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Oxidative Stress
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Plasmids / chemistry
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Plasmids / metabolism
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Primary Cell Culture
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / antagonists & inhibitors*
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Reactive Oxygen Species / metabolism
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Signal Transduction
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transfection
Substances
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Biomarkers
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, rat
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Reactive Oxygen Species
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Transcription Factors
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8-Hydroxy-2'-Deoxyguanosine
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Dnm1l protein, rat
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Dynamins
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Deoxyguanosine
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Glucose
Grants and funding
This work was supported by the Major State Basic Research Development Program of China (973 program) #2012CB517700, grants from the National Natural Science Foundation of China #81070649, the Plan for New hundred people of Shanghai Jiao Tong University, the EFSD/CDS/Lilly Programme for Collaborative Research between China and Europe, and the Shanghai Pujiang Program #14PJD025 (to H Chen). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.