Transforming Growth Factor-β induced cross talk between p53 and a microRNA in the pathogenesis of Diabetic Nephropathy

  1. Rama Natarajan1,2
  1. 1Irell & Manella Graduate School of Biological Sciences
  2. 2Department of Diabetes and Division of Molecular Diabetes Research, Beckman Research Institute of the City of Hope, Duarte, CA.
  3. 3Internal medicine, University of Michigan, Ann Arbor, MI
  4. 4National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
  1. Corresponding Authors: Rama Natarajan RNatarajan{at}coh.org, Mitsuo Kato mkato{at}coh.org

Abstract

Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However the mechanisms are unclear. We report that expression levels of transforming growth factor-β1 (TGF-β), p53 and microRNA-192 (miR-192), are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to non-diabetic mice. Targeting miR-192 with locked-nucleic-acid modified inhibitors (LNA-192) in vivo decreases expression of p53 in the renal cortex of control and streptozotocin injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-β and p53 expression when made diabetic, and reduced renal fibrosis, hypertrophy, proteinuria and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-β induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-β-induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR-192-knockout mice are protected from key features of DN.

  • Received February 21, 2013.
  • Accepted April 27, 2013.

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This Article

  1. Diabetes
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