The TGFβ (transforming growth factor β)/SMAD and NF-κB (nuclear factor κB) signalling pathways play a key role in hypertensive nephropathy. The present study examined whether targeting these pathways by SMAD7, a downstream inhibitor of both pathways, blocks AngII (angiotensin II)-induced hypertensive kidney disease in mice. A doxycycline-inducible SMAD7-expressing plasmid was delivered into the kidney by a non-invasive ultrasound-microbubble technique before and after AngII infusion. Results showed that pre-treatment with SMAD7 prevented AngII-induced progressive renal injury by inhibiting an increase in proteinuria and serum creatinine while improving the glomerular filtration rate. Similarly, treatment with SMAD7 in the established hypertensive nephropathy at day 14 after AngII infusion halted the progressive renal injury. These preventive and therapeutic effects of SMAD7 on hypertensive kidney injury were associated with inhibition of AngII-induced up-regulation of SMURF2 (SMAD-specific E3 ubiquitin protein ligase 2) and Sp1 (specificity protein 1), blockade of TGFβ/Smad3-mediated renal fibrosis and suppression of NF-κB-driven renal inflammation. Moreover, overexpression of SMAD7 also prevented AngII-induced loss of renal miR-29b, an miRNA with an inhibitory role in both TGFβ/Smad3 and NF-κB pathways. In conclusion, SMAD7 may be a therapeutic agent for AngII-mediated hypertensive nephropathy. Inhibition of the Sp1/SMAD3/NF-κB/miR-29b regulatory network may be a mechanism by which SMAD7 inhibits hypertensive nephropathy.
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Research Article|
April 03 2014
Smad7 inhibits AngII-mediated hypertensive nephropathy in a mouse model of hypertension
Guan-Xian Liu;
Guan-Xian Liu
1
*Department of Nephrology, Central Municipal Hospital of Huizhou, Huizhou, Guangdong, China
Correspondence: Professor Guan-Xian Liu (email [email protected]) or Professor Hui Yao Lan (email [email protected]).
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You-Qi Li;
You-Qi Li
1
*Department of Nephrology, Central Municipal Hospital of Huizhou, Huizhou, Guangdong, China
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Xiao R. Huang;
Xiao R. Huang
†Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Hong Kong SAR, China
‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Li Hua Wei;
Li Hua Wei
‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Yang Zhang;
Yang Zhang
‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Min Feng;
Min Feng
‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Xiao-Ming Meng;
Xiao-Ming Meng
‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Hai-Yong Chen;
Hai-Yong Chen
‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Yong-Jun Shi;
Yong-Jun Shi
*Department of Nephrology, Central Municipal Hospital of Huizhou, Huizhou, Guangdong, China
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Hui Y. Lan
†Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Hong Kong SAR, China
‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
Correspondence: Professor Guan-Xian Liu (email [email protected]) or Professor Hui Yao Lan (email [email protected]).
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Publisher: Portland Press Ltd
Received:
November 04 2013
Revision Received:
January 30 2014
Accepted:
February 11 2014
Accepted Manuscript online:
February 11 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (3): 195–208.
Article history
Received:
November 04 2013
Revision Received:
January 30 2014
Accepted:
February 11 2014
Accepted Manuscript online:
February 11 2014
Citation
Guan-Xian Liu, You-Qi Li, Xiao R. Huang, Li Hua Wei, Yang Zhang, Min Feng, Xiao-Ming Meng, Hai-Yong Chen, Yong-Jun Shi, Hui Y. Lan; Smad7 inhibits AngII-mediated hypertensive nephropathy in a mouse model of hypertension. Clin Sci (Lond) 1 August 2014; 127 (3): 195–208. doi: https://doi.org/10.1042/CS20130706
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