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, Beckman Research Institute of the City of Hope, Duarte, California
- 2Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
- 3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- 4National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
- Corresponding authors: Rama Natarajan, , and 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 nondiabetic mice. Targeting miR-192 with locked nucleic acid–modified inhibitors 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 have 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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