title: Smad7 inhibits AngII-mediated hypertensive nephropathy in a mouse model of hypertension.
abstract: 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.
authors: *Department of Nephrology, Central Municipal Hospital of Huizhou, Huizhou, Guangdong, China.
authors: Guan-Xian
authors: GX
authors: Liu
authors: *Department of Nephrology, Central Municipal Hospital of Huizhou, Huizhou, Guangdong, China.
authors: You-Qi
authors: YQ
authors: Li
authors: Xiao R
authors: XR
authors: Huang
authors: ‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors: Li Hua
authors: LH
authors: Wei
authors: ‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors: Yang
authors: Y
authors: Zhang
authors: ‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors: Min
authors: M
authors: Feng
authors: ‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors: Xiao-Ming
authors: XM
authors: Meng
authors: ‡Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors: Hai-Yong
authors: HY
authors: Chen
authors: *Department of Nephrology, Central Municipal Hospital of Huizhou, Huizhou, Guangdong, China.
authors: Yong-Jun
authors: YJ
authors: Shi
authors: Hui Y
authors: HY
authors: Lan
mesh_terms: D000804:Angiotensin II; D000818:Animals; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006977:Hypertension, Renal / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II