Smad7 plays a protective role in chronic kidney disease; however, its role in acute kidney injury (AKI) remains unexplored. Here, we report that Smad7 protects against AKI by rescuing the G1 cell cycle arrest of tubular epithelial cells (TECs) in ischemia/reperfusion-induced AKI in mice in which Smad7 gene is disrupted or restored locally into the kidney. In Smad7 gene knockout (KO) mice, more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis was developed at 48 h after AKI. In contrast, restored renal Smad7 gene locally into the kidney of Smad7 KO mice protected against AKI by promoting TEC proliferation identified by PCNA+ and BrdU+ cells. Mechanistic studies revealed that worsen AKI in Smad7 KO mice was associated with a marked activation of TGF-β/Smad3-p21/p27 signaling and a loss of CDK2/cyclin E activities, thereby impairing TEC regeneration at the G1 cell cycle arrest. In contrast, restored Smad7 locally into the kidneys of Smad7 KO mice protected TECs from the G1 cell cycle arrest and promoted TEC G1/S transition via a CDK2/cyclin E-dependent mechanism. In conclusion, Smad7 plays a protective role in AKI. Blockade of TGF-β/Smad3-p21/p27-induced G1 cell cycle arrest may be a key mechanism by which Smad7 treatment inhibits AKI. Thus, Smad7 may be a novel therapeutic agent for AKI.
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August 2017
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Cover Image
Human vascular smooth muscle cell derived from a skin precursor. Subjects with type-2 diabetes have fewer skin-derived precursors in their skin. Vascular smooth muscle cells derived from skin-derived precursors from subjects with type-2 diabetes carry persistent signatures of disease even weeks after being removed from the patient. Thus, skin-derived precursors may be a promising platform to study type-2 diabetes associated vascular disease in a dish. In Clinical Science volume 131, issue 15, Steinbach et al. describe new approach to studying human vascular smooth muscle cell (VSMC) pathophysiology by examining VSMCs differentiated from progenitors found in skin (see pages 1801-1814).
Research Article|
July 13 2017
Smad7 protects against acute kidney injury by rescuing tubular epithelial cells from the G1 cell cycle arrest
Sha Fu;
Sha Fu
*
1Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
2Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, China
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Ying Tang;
Ying Tang
*
1Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Xiao R. Huang;
Xiao R. Huang
2Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, China
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Min Feng;
Min Feng
1Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
2Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, China
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An P. Xu;
1Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
Correspondence: Hui Y. Lan ([email protected]) or Anping Xu ([email protected])
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Hui Y. Lan
2Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, China
Correspondence: Hui Y. Lan ([email protected]) or Anping Xu ([email protected])
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Publisher: Portland Press Ltd
Received:
February 07 2017
Revision Received:
May 30 2017
Accepted:
May 31 2017
Accepted Manuscript online:
May 31 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (15): 1955–1969.
Article history
Received:
February 07 2017
Revision Received:
May 30 2017
Accepted:
May 31 2017
Accepted Manuscript online:
May 31 2017
Citation
Sha Fu, Ying Tang, Xiao R. Huang, Min Feng, An P. Xu, Hui Y. Lan; Smad7 protects against acute kidney injury by rescuing tubular epithelial cells from the G1 cell cycle arrest. Clin Sci (Lond) 1 August 2017; 131 (15): 1955–1969. doi: https://doi.org/10.1042/CS20170127
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