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Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy

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,...

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Autores principales: Deshpande, Supriya D., Putta, Sumanth, Wang, Mei, Lai, Jennifer Y., Bitzer, Markus, Nelson, Robert G., Lanting, Linda L., Kato, Mitsuo, Natarajan, Rama
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749352/
https://www.ncbi.nlm.nih.gov/pubmed/23649518
http://dx.doi.org/10.2337/db13-0305
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author Deshpande, Supriya D.
Putta, Sumanth
Wang, Mei
Lai, Jennifer Y.
Bitzer, Markus
Nelson, Robert G.
Lanting, Linda L.
Kato, Mitsuo
Natarajan, Rama
author_facet Deshpande, Supriya D.
Putta, Sumanth
Wang, Mei
Lai, Jennifer Y.
Bitzer, Markus
Nelson, Robert G.
Lanting, Linda L.
Kato, Mitsuo
Natarajan, Rama
author_sort Deshpande, Supriya D.
collection PubMed
description 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.
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spelling pubmed-37493522014-09-01 Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy Deshpande, Supriya D. Putta, Sumanth Wang, Mei Lai, Jennifer Y. Bitzer, Markus Nelson, Robert G. Lanting, Linda L. Kato, Mitsuo Natarajan, Rama Diabetes Original Research 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. American Diabetes Association 2013-09 2013-08-15 /pmc/articles/PMC3749352/ /pubmed/23649518 http://dx.doi.org/10.2337/db13-0305 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Deshpande, Supriya D.
Putta, Sumanth
Wang, Mei
Lai, Jennifer Y.
Bitzer, Markus
Nelson, Robert G.
Lanting, Linda L.
Kato, Mitsuo
Natarajan, Rama
Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy
title Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy
title_full Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy
title_fullStr Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy
title_full_unstemmed Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy
title_short Transforming Growth Factor-β–Induced Cross Talk Between p53 and a MicroRNA in the Pathogenesis of Diabetic Nephropathy
title_sort transforming growth factor-β–induced cross talk between p53 and a microrna in the pathogenesis of diabetic nephropathy
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749352/
https://www.ncbi.nlm.nih.gov/pubmed/23649518
http://dx.doi.org/10.2337/db13-0305
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