title: Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury.
abstract: 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.
authors: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Research Program in Mitochondrial Therapeutics, Weill Cornell Medical College, New York, New York, USA. Electronic address: hhszeto@med.cornell.edu.
authors: Hazel H
authors: HH
authors: Szeto
authors: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Research Program in Mitochondrial Therapeutics, Weill Cornell Medical College, New York, New York, USA.
authors: Shaoyi
authors: S
authors: Liu
authors: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Research Program in Mitochondrial Therapeutics, Weill Cornell Medical College, New York, New York, USA.
authors: Yi
authors: Y
authors: Soong
authors: Department of Physiology, Weill Cornell Medical College, New York, New York, USA; Burke Medical Research Institute, White Plains, New York, USA.
authors: Nazia
authors: N
authors: Alam
authors: Department of Physiology, Weill Cornell Medical College, New York, New York, USA; Burke Medical Research Institute, White Plains, New York, USA.
authors: Glen T
authors: GT
authors: Prusky
authors: Department of Pathology, Weill Cornell Medical College, New York, New York, USA.
authors: Surya V
authors: SV
authors: Seshan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005921:Glomerulonephritis / Q000209:etiology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000648:ultrastructure; D050356:Lipid Metabolism / Q000187:drug effects; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D009765:Obesity / Q000150:complications; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D050199:Podocytes / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D055372:AMP-Activated Protein Kinases
keywords: endothelium; fibrosis; inflammation; mitochondria; obesity; podocyte