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Transforming growth factor-β-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic

Supriya D Deshpande1, Sumanth Putta, Mei Wang

  • 1Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California, USA.

Diabetes
|May 8, 2013
PubMed

Insights

Transforming growth factor-β1 (TGF-β) induces a feedback loop between p53 and microRNA-192 (miR-192), driving diabetic nephropathy (DN) progression. Inhibiting miR-192 or its genetic deletion protects against DN.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Diabetic nephropathy (DN) is a complication of diabetes, characterized by kidney damage.
  • Elevated p53 expression is linked to kidney diseases, but its role in DN pathogenesis is not fully understood.
  • Transforming growth factor-β1 (TGF-β) and microRNA-192 (miR-192) are implicated in kidney fibrosis.

Purpose of the Study:

  • To elucidate the mechanisms linking p53, TGF-β, and miR-192 in diabetic nephropathy.
  • To investigate the therapeutic potential of targeting the miR-192/p53 axis in DN.

Main Methods:

  • Analysis of p53, TGF-β, and miR-192 expression in renal cortex of diabetic and control mice.
  • In vivo inhibition of miR-192 using locked nucleic acid-modified inhibitors.
  • Generation and study of miR-192 knockout mice subjected to diabetes induction.
  • In vitro promoter assays to determine regulatory relationships.
  • Correlation analysis of miR-192 and Zeb2 in human DN glomeruli.

Main Results:

  • Diabetic mice exhibited increased renal TGF-β, p53, and miR-192 expression, correlating with glomerular fibrosis.
  • miR-192 inhibition reduced p53 expression in diabetic mice.
  • miR-192 knockout mice showed attenuated TGF-β and p53 levels, with reduced DN features (fibrosis, hypertrophy, proteinuria).
  • TGF-β induced a feedback loop between miR-192 and p53 via Zeb2, promoting DN.
  • Inverse correlation between miR-192 and Zeb2 observed in human DN samples.

Conclusions:

  • A novel TGF-β-induced feedback loop between p53 and miR-192 contributes to DN pathogenesis.
  • Targeting miR-192 offers a potential therapeutic strategy for diabetic nephropathy.
  • miR-192 deficiency protects against key pathological features of diabetic nephropathy.

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