Disruption of Smad7 promotes ANG II-mediated renal inflammation and fibrosis via Sp1-TGF-β/Smad3-NF.κB-dependent mechanisms in mice

Smad7 is an inhibitory Smad and plays a protective role in obstructive and diabetic kidney disease. However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced h...

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Published in:PloS one 2013, Vol.8 (1), p.e53573-e53573
Main Authors: Liu, Guan-Xian, Li, You-Qi, Huang, Xiao R, Wei, Lihua, Chen, Hai-Yong, Shi, Yong-Jun, Heuchel, Rainer L, Lan, Hui Y
Format: Article
Language:English
Subjects:
Angiotensin II
Angiotensin II - metabolism
Animals
Biology
Blood pressure
Cell activation
Cell- och molekylärbiologi
Collagen
Diabetes mellitus
Endokrinologi och diabetes
Fibrosis
Gene Expression Regulation
Growth factors
Health sciences
Histology
Hospitals
Hypertension
Hypertension - metabolism
IL-1β
Infiltration
Inflammation
Inflammation - pathology
Injury prevention
Kidney - metabolism
Kidney diseases
Kidney Diseases - metabolism
Kinases
Klinisk medicin
Macrophages
Male
Medicin och hälsovetenskap
Medicine
Medicinska och farmaceutiska grundvetenskaper
Mice
Mice, Knockout
MicroRNAs - metabolism
Nephrology
Nephropathy
NF-kappa B - metabolism
NF-κB protein
Proteins
Proteinuria
Proteinuria - metabolism
Regulatory mechanisms (biology)
Renal function
Rodents
Signal Transduction
Signaling
Smad protein
Smad3 protein
Smad3 Protein - metabolism
Smad7 protein
Smad7 Protein - genetics
Sp1 protein
Sp1 Transcription Factor - metabolism
Transforming Growth Factor beta - metabolism
Transforming growth factor-b1
Tumor necrosis factor-α
Urine
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cited_by cdi_FETCH-LOGICAL-c4913-3b13b092d8921489144af38eb85631b64f6bace2aa31be7d1d7c044073a8afc93
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creator Liu, Guan-Xian
Li, You-Qi
Huang, Xiao R
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description Smad7 is an inhibitory Smad and plays a protective role in obstructive and diabetic kidney disease. However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced hypertensive nephropathy. Smad7 gene knockout (KO) and wild-type (WT) mice received a subcutaneous infusion of ANG II or control saline for 4 weeks via osmotic mini-pumps. ANG II infusion produced equivalent hypertension in Smad7 KO and WT mice; however, Smad7 KO mice exhibited more severe renal functional injury as shown by increased proteinuria and reduced renal function (both p
doi_str_mv 10.1371/journal.pone.0053573
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However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced hypertensive nephropathy. Smad7 gene knockout (KO) and wild-type (WT) mice received a subcutaneous infusion of ANG II or control saline for 4 weeks via osmotic mini-pumps. ANG II infusion produced equivalent hypertension in Smad7 KO and WT mice; however, Smad7 KO mice exhibited more severe renal functional injury as shown by increased proteinuria and reduced renal function (both p&lt;0.05) when compared with Smad7 WT mice. Enhanced renal injury in Smad7 KO mice was associated with more progressive renal fibrosis with elevated TGF-β/Smad3 signalling. Smad7 KO mice also showed more profound renal inflammation including increased macrophage infiltration, enhanced IL-1β and TNF-α expression, and a marked activation of NF-κB signaling (all p&lt;0.01). Further studies revealed that enhanced ANG II-mediated renal inflammation and fibrosis in Smad7 KO mice were also associated with up-regulation of Sp1 but downregulation of miR-29b expression. Taken together, the present study revealed that enhanced Sp1-TGF-β1/Smad3-NF-κB signaling and loss of miR-29 may be mechanisms by which deletion of Smad7 promotes ANG II-mediated renal fibrosis and inflammation. Thus, Smad7 may play a protective role in ANG II-induced hypertensive kidney disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0053573</identifier><identifier>PMID: 23301086</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiotensin II ; Angiotensin II - metabolism ; Animals ; Biology ; Blood pressure ; Cell activation ; Cell- och molekylärbiologi ; Collagen ; Diabetes mellitus ; Endokrinologi och diabetes ; Fibrosis ; Gene Expression Regulation ; Growth factors ; Health sciences ; Histology ; Hospitals ; Hypertension ; Hypertension - metabolism ; IL-1β ; Infiltration ; Inflammation ; Inflammation - pathology ; Injury prevention ; Kidney - metabolism ; Kidney diseases ; Kidney Diseases - metabolism ; Kinases ; Klinisk medicin ; Macrophages ; Male ; Medicin och hälsovetenskap ; Medicine ; Medicinska och farmaceutiska grundvetenskaper ; Mice ; Mice, Knockout ; MicroRNAs - metabolism ; Nephrology ; Nephropathy ; NF-kappa B - metabolism ; NF-κB protein ; Proteins ; Proteinuria ; Proteinuria - metabolism ; Regulatory mechanisms (biology) ; Renal function ; Rodents ; Signal Transduction ; Signaling ; Smad protein ; Smad3 protein ; Smad3 Protein - metabolism ; Smad7 protein ; Smad7 Protein - genetics ; Sp1 protein ; Sp1 Transcription Factor - metabolism ; Transforming Growth Factor beta - metabolism ; Transforming growth factor-b1 ; Tumor necrosis factor-α ; Urine</subject><ispartof>PloS one, 2013, Vol.8 (1), p.e53573-e53573</ispartof><rights>2013 Liu et al. 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However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced hypertensive nephropathy. Smad7 gene knockout (KO) and wild-type (WT) mice received a subcutaneous infusion of ANG II or control saline for 4 weeks via osmotic mini-pumps. ANG II infusion produced equivalent hypertension in Smad7 KO and WT mice; however, Smad7 KO mice exhibited more severe renal functional injury as shown by increased proteinuria and reduced renal function (both p&lt;0.05) when compared with Smad7 WT mice. Enhanced renal injury in Smad7 KO mice was associated with more progressive renal fibrosis with elevated TGF-β/Smad3 signalling. Smad7 KO mice also showed more profound renal inflammation including increased macrophage infiltration, enhanced IL-1β and TNF-α expression, and a marked activation of NF-κB signaling (all p&lt;0.01). Further studies revealed that enhanced ANG II-mediated renal inflammation and fibrosis in Smad7 KO mice were also associated with up-regulation of Sp1 but downregulation of miR-29b expression. Taken together, the present study revealed that enhanced Sp1-TGF-β1/Smad3-NF-κB signaling and loss of miR-29 may be mechanisms by which deletion of Smad7 promotes ANG II-mediated renal fibrosis and inflammation. 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metabolism</topic><topic>Animals</topic><topic>Biology</topic><topic>Blood pressure</topic><topic>Cell activation</topic><topic>Cell- och molekylärbiologi</topic><topic>Collagen</topic><topic>Diabetes mellitus</topic><topic>Endokrinologi och diabetes</topic><topic>Fibrosis</topic><topic>Gene Expression Regulation</topic><topic>Growth factors</topic><topic>Health sciences</topic><topic>Histology</topic><topic>Hospitals</topic><topic>Hypertension</topic><topic>Hypertension - metabolism</topic><topic>IL-1β</topic><topic>Infiltration</topic><topic>Inflammation</topic><topic>Inflammation - pathology</topic><topic>Injury prevention</topic><topic>Kidney - metabolism</topic><topic>Kidney diseases</topic><topic>Kidney Diseases - metabolism</topic><topic>Kinases</topic><topic>Klinisk medicin</topic><topic>Macrophages</topic><topic>Male</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicine</topic><topic>Medicinska och farmaceutiska grundvetenskaper</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>MicroRNAs - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Guan-Xian</au><au>Li, You-Qi</au><au>Huang, Xiao R</au><au>Wei, Lihua</au><au>Chen, Hai-Yong</au><au>Shi, Yong-Jun</au><au>Heuchel, Rainer L</au><au>Lan, Hui Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disruption of Smad7 promotes ANG II-mediated renal inflammation and fibrosis via Sp1-TGF-β/Smad3-NF.κB-dependent mechanisms in mice</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013</date><risdate>2013</risdate><volume>8</volume><issue>1</issue><spage>e53573</spage><epage>e53573</epage><pages>e53573-e53573</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Competing Interests: The authors have declared that no competing interests exist.</notes><notes>Conceived and designed the experiments: GXL HYL. Performed the experiments: YQL XRH LW. Analyzed the data: HYC YJS. Contributed reagents/materials/analysis tools: RLH. Wrote the paper: YQL RLH HYL.</notes><abstract>Smad7 is an inhibitory Smad and plays a protective role in obstructive and diabetic kidney disease. However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced hypertensive nephropathy. Smad7 gene knockout (KO) and wild-type (WT) mice received a subcutaneous infusion of ANG II or control saline for 4 weeks via osmotic mini-pumps. ANG II infusion produced equivalent hypertension in Smad7 KO and WT mice; however, Smad7 KO mice exhibited more severe renal functional injury as shown by increased proteinuria and reduced renal function (both p&lt;0.05) when compared with Smad7 WT mice. Enhanced renal injury in Smad7 KO mice was associated with more progressive renal fibrosis with elevated TGF-β/Smad3 signalling. Smad7 KO mice also showed more profound renal inflammation including increased macrophage infiltration, enhanced IL-1β and TNF-α expression, and a marked activation of NF-κB signaling (all p&lt;0.01). Further studies revealed that enhanced ANG II-mediated renal inflammation and fibrosis in Smad7 KO mice were also associated with up-regulation of Sp1 but downregulation of miR-29b expression. Taken together, the present study revealed that enhanced Sp1-TGF-β1/Smad3-NF-κB signaling and loss of miR-29 may be mechanisms by which deletion of Smad7 promotes ANG II-mediated renal fibrosis and inflammation. Thus, Smad7 may play a protective role in ANG II-induced hypertensive kidney disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23301086</pmid><doi>10.1371/journal.pone.0053573</doi><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2013, Vol.8 (1), p.e53573-e53573
issn 1932-6203
1932-6203
language eng
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source Publicly Available Content Database; PubMed Central
subjects Angiotensin II
Angiotensin II - metabolism
Animals
Biology
Blood pressure
Cell activation
Cell- och molekylärbiologi
Collagen
Diabetes mellitus
Endokrinologi och diabetes
Fibrosis
Gene Expression Regulation
Growth factors
Health sciences
Histology
Hospitals
Hypertension
Hypertension - metabolism
IL-1β
Infiltration
Inflammation
Inflammation - pathology
Injury prevention
Kidney - metabolism
Kidney diseases
Kidney Diseases - metabolism
Kinases
Klinisk medicin
Macrophages
Male
Medicin och hälsovetenskap
Medicine
Medicinska och farmaceutiska grundvetenskaper
Mice
Mice, Knockout
MicroRNAs - metabolism
Nephrology
Nephropathy
NF-kappa B - metabolism
NF-κB protein
Proteins
Proteinuria
Proteinuria - metabolism
Regulatory mechanisms (biology)
Renal function
Rodents
Signal Transduction
Signaling
Smad protein
Smad3 protein
Smad3 Protein - metabolism
Smad7 protein
Smad7 Protein - genetics
Sp1 protein
Sp1 Transcription Factor - metabolism
Transforming Growth Factor beta - metabolism
Transforming growth factor-b1
Tumor necrosis factor-α
Urine
title Disruption of Smad7 promotes ANG II-mediated renal inflammation and fibrosis via Sp1-TGF-β/Smad3-NF.κB-dependent mechanisms in mice
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