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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
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.
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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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