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Regulation of PTEN/AKT/FAK pathways by PPARγ impacts on fibrosis in diabetic nephropathy

Rui Yan1, Yuanyuan Wang2, Mingjun Shi2

  • 1Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.

Journal of Cellular Biochemistry
|January 18, 2019
PubMed

Insights

Peroxisome proliferator-activated receptors γ (PPARγ) regulate phosphatase and tensin homolog (PTEN) expression, influencing diabetic nephropathy (DN) progression. This pathway impacts renal tubular epithelial-to-mesenchymal transition and tubulointerstitial fibrosis.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • Diabetic nephropathy (DN) is characterized by renal tubular epithelial-to-mesenchymal transition (EMT) and tubulointerstitial fibrosis (TIF).
  • The precise regulatory mechanisms of EMT and TIF in DN remain incompletely understood.
  • Reduced phosphatase and tensin homolog (PTEN) expression is linked to DN severity, but its role in EMT and TIF is unclear.

Purpose of the Study:

  • To investigate the mechanism by which peroxisome proliferator-activated receptors γ (PPARγ) regulate PTEN expression and its subsequent impact on EMT and TIF in diabetic nephropathy.
  • To elucidate the role of PTEN's dual lipid and protein phosphatase activities, modulated by the AKT/FAK signaling pathway, in DN pathogenesis.

Main Methods:

  • Utilized rat proximal tubular epithelial cells (NRK52E), C57BL mice, and human kidney tissues.
  • Investigated the transcriptional regulation of PTEN by PPARγ.
  • Analyzed the influence of PTEN's lipid and protein phosphatase activities on the AKT/FAK signaling pathway and EMT/TIF.

Main Results:

  • PPARγ was found to regulate PTEN expression transcriptionally, thereby influencing EMT and TIF.
  • PTEN's dual phosphatase activity impacts AKT and FAK phosphorylation and FAK transcription.
  • A PTEN mutant (PTEN-G129E) lacking lipid phosphatase activity demonstrated that its protein phosphatase activity is crucial for EMT and fibrosis via FAK phosphorylation.

Conclusions:

  • The PPARγ/PTEN/AKT/FAK signaling pathway plays a systematic role in the pathogenesis of EMT and TIF in diabetic nephropathy.
  • PTEN's phosphatase activities are critical regulators of renal fibrosis in DN.
  • Targeting the PPARγ/PTEN axis offers a potential therapeutic strategy for DN.
Keywords:
diabetic nephropathyepithelial-to-mesenchymal transitionperoxisome proliferator-activated receptors γphosphatase and tensin homolog deleted on chromosome 10renal tubulointerstitial fibrosis

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