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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes

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Oxidative stress-induced alterations in PPAR-γ and associated mitochondrial destabilization contribute to kidney cell

David M Small1, Christudas Morais1, Jeff S Coombes2

  • 1Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia;

American Journal of Physiology. Renal Physiology
|August 15, 2014
PubMed

Insights

PPAR-γ agonists worsen kidney proximal tubular epithelium damage from oxidative stress. This study found PPAR-γ activation detrimental to kidney cells under oxidative stress, contrary to other tissues.

Area of Science:

  • Nephrology
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Mitochondrial dysfunction and oxidative stress are key factors in kidney disease.
  • The protective mechanisms of peroxisome proliferator-activated receptor (PPAR)-γ agonists in kidney disease are not fully understood.
  • PPAR-γ is known to regulate proteins involved in mitochondrial biogenesis.

Purpose of the Study:

  • To investigate the role of PPAR-γ in protecting kidney proximal tubular epithelium (PTE) against mitochondrial destabilization and oxidative stress.
  • To determine the effects of PPAR-γ activation on PTE cells under induced oxidative conditions.

Main Methods:

  • HK-2 PTE cells were exposed to hydrogen peroxide (H₂O₂) to induce oxidative stress.
  • Assessed apoptosis, cell viability (MTT assay), superoxide production, mitochondrial function (MitoTracker red, JC-1), ATP levels, and mitochondrial ultrastructure via electron microscopy.
  • Investigated protein expression of PPAR-γ, phospho-PPAR-γ, PGC-1α, Parkin (Park2), p62, and LC3β using Western blots.
  • Modulated PPAR-γ activity using agonists rosiglitazone, pioglitazone, and troglitazone.

Main Results:

  • Oxidative stress led to mitochondrial destabilization, decreased ATP levels, loss of mitochondrial membrane potential, and increased superoxide production.
  • Electron microscopy revealed sparse mitochondria with disrupted cristae.
  • Mitophagy was initially observed but became impaired with p62 accumulation.
  • PPAR-γ expression decreased, while phospho-PPAR-γ increased, and PGC-1α decreased, indicating aberrant PPAR-γ activation and reduced mitochondrial biogenesis.
  • Cell viability decreased, and PPAR-γ agonists exacerbated apoptosis.

Conclusions:

  • Oxidative stress induces mitochondrial destabilization in kidney PTE, associated with increased PPAR-γ phosphorylation.
  • PPAR-γ agonists did not protect PTE cells and, in fact, promoted apoptosis.
  • PPAR-γ activation appears detrimental to kidney PTE health under conditions of oxidative stress, despite potential benefits in other tissues.
Keywords:
mitochondriaoxidative stressperoxisome proliferator-activated receptor-γthiozolidinediones

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