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Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy
Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-deriv...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964498/ https://www.ncbi.nlm.nih.gov/pubmed/24353183 http://dx.doi.org/10.2337/db13-1412 |
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author | Xiao, Li Zhu, Xuejing Yang, Shikun Liu, Fuyou Zhou, Zhiguang Zhan, Ming Xie, Ping Zhang, Dongshan Li, Jun Song, Panai Kanwar, Yashpal S. Sun, Lin |
author_facet | Xiao, Li Zhu, Xuejing Yang, Shikun Liu, Fuyou Zhou, Zhiguang Zhan, Ming Xie, Ping Zhang, Dongshan Li, Jun Song, Panai Kanwar, Yashpal S. Sun, Lin |
author_sort | Xiao, Li |
collection | PubMed |
description | Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress. The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN were examined in rats with streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-β and PGC-1α. Furthermore, Rap1b G12V also decreased phosphorylation of Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-β or PGC-1α short interfering RNA. In addition, Rap1b could modulate C/EBP-β binding to the endogenous PGC-1α promoter and the interaction between PGC-1α and catalase or mitochondrial superoxide dismutase, indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-β–PGC-1α signaling. |
format | Online Article Text |
id | pubmed-3964498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-39644982015-04-01 Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy Xiao, Li Zhu, Xuejing Yang, Shikun Liu, Fuyou Zhou, Zhiguang Zhan, Ming Xie, Ping Zhang, Dongshan Li, Jun Song, Panai Kanwar, Yashpal S. Sun, Lin Diabetes Complications Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress. The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN were examined in rats with streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-β and PGC-1α. Furthermore, Rap1b G12V also decreased phosphorylation of Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-β or PGC-1α short interfering RNA. In addition, Rap1b could modulate C/EBP-β binding to the endogenous PGC-1α promoter and the interaction between PGC-1α and catalase or mitochondrial superoxide dismutase, indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-β–PGC-1α signaling. American Diabetes Association 2014-04 2014-03-13 /pmc/articles/PMC3964498/ /pubmed/24353183 http://dx.doi.org/10.2337/db13-1412 Text en © 2014 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 | Complications Xiao, Li Zhu, Xuejing Yang, Shikun Liu, Fuyou Zhou, Zhiguang Zhan, Ming Xie, Ping Zhang, Dongshan Li, Jun Song, Panai Kanwar, Yashpal S. Sun, Lin Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy |
title | Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy |
title_full | Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy |
title_fullStr | Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy |
title_full_unstemmed | Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy |
title_short | Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy |
title_sort | rap1 ameliorates renal tubular injury in diabetic nephropathy |
topic | Complications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964498/ https://www.ncbi.nlm.nih.gov/pubmed/24353183 http://dx.doi.org/10.2337/db13-1412 |
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