Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury

Kidney Int. 2016 Nov;90(5):997-1011. doi: 10.1016/j.kint.2016.06.013. Epub 2016 Aug 9.


Obesity is a major risk factor for the development of chronic kidney disease, even independent of its association with hypertension, diabetes, and dyslipidemia. The primary pathologic finding of obesity-related kidney disease is glomerulopathy, with glomerular hypertrophy, mesangial matrix expansion, and focal segmental glomerulosclerosis. Proposed mechanisms leading to renal pathology include abnormal lipid metabolism, lipotoxicity, inhibition of AMP kinase, and endoplasmic reticulum stress. Here we report dramatic changes in mitochondrial structure in glomerular endothelial cells, podocytes, and proximal tubular epithelial cells after 28 weeks of a high-fat diet in C57BL/6 mice. Treatment with SS-31, a tetrapeptide that targets cardiolipin and protects mitochondrial cristae structure, during high-fat diet preserved normal mitochondrial structure in all kidney cells, restored renal AMP kinase activity, and prevented intracellular lipid accumulation, endoplasmic reticulum stress, and apoptosis. SS-31 had no effect on weight gain, insulin resistance or hyperglycemia. However, SS-31 prevented loss of glomerular endothelial cells and podocytes, mesangial expansion, glomerulosclerosis, macrophage infiltration, and upregulation of proinflammatory (TNF-α, MCP-1, NF-κB) and profibrotic (TGF-β) cytokines. Thus, mitochondria protection can overcome lipotoxicity in the kidney and represent a novel upstream target for therapeutic development.

Keywords: endothelium; fibrosis; inflammation; mitochondria; obesity; podocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Apoptosis / drug effects
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Capillaries / drug effects
  • Diet, High-Fat / adverse effects*
  • Drug Evaluation, Preclinical
  • Endoplasmic Reticulum Stress / drug effects
  • Endothelium, Vascular / drug effects
  • Glomerulonephritis / etiology
  • Glomerulonephritis / prevention & control*
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / ultrastructure
  • Lipid Metabolism / drug effects
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Mitochondria / drug effects*
  • Mitochondria / ultrastructure
  • Obesity / complications
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use*
  • Podocytes / drug effects


  • Blood Glucose
  • Oligopeptides
  • arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
  • AMP-Activated Protein Kinases