Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice

Diabetologia. 2013 Jan;56(1):204-17. doi: 10.1007/s00125-012-2747-2. Epub 2012 Oct 23.


Aims/hypothesis: Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes.

Methods: Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks.

Results: The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1α signalling and of the key downstream effectors, the PPARα-oestrogen-related receptor (ERR)-1α-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling and the downstream effectors, PPARα-ERR-1α-SREBP1.

Conclusions/interpretation: The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / chemistry
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / prevention & control*
  • Enzyme Activation / drug effects
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney / physiopathology
  • Lipid Metabolism / drug effects
  • Lipotropic Agents / pharmacology
  • Lipotropic Agents / therapeutic use
  • Male
  • Mesangial Cells / drug effects*
  • Mesangial Cells / metabolism
  • Mesangial Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Oxidative Stress / drug effects
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use*
  • Protein Processing, Post-Translational / drug effects
  • RNA Interference
  • Resveratrol
  • Signal Transduction / drug effects*
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / chemistry
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Stilbenes / pharmacology
  • Stilbenes / therapeutic use*
  • Transcription Factors / agonists
  • Transcription Factors / metabolism


  • Lipotropic Agents
  • Protective Agents
  • Stilbenes
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • AMP-Activated Protein Kinases
  • Sirt1 protein, rat
  • Sirtuin 1
  • Resveratrol