Transforming Growth Factor-β induced cross talk between p53 and a microRNA in the pathogenesis of Diabetic Nephropathy
- Supriya D. Deshpande1,2,
- Sumanth Putta2,
- Mei Wang2,
- Jennifer Y. Lai3,
- Markus Bitzer3,
- Robert G. Nelson4,
- Linda L. Lanting2,
- Mitsuo Kato2 and
- Rama Natarajan1,2
- 1Irell & Manella Graduate School of Biological Sciences
- 2Department of Diabetes and Division of Molecular Diabetes Research, Beckman Research Institute of the City of Hope, Duarte, CA.
- 3Internal medicine, University of Michigan, Ann Arbor, MI
- 4National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
- Corresponding Authors: Rama Natarajan , Mitsuo Kato
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.
- © 2013 by the American Diabetes Association.
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