Document Detail

Sonic hedgehog signaling mediates epithelial-mesenchymal communication and promotes renal fibrosis.
MedLine Citation:
PMID:  22302193     Owner:  NLM     Status:  MEDLINE    
Sonic hedgehog (Shh) signaling is a developmental signal cascade that plays an essential role in regulating embryogenesis and tissue homeostasis. Here, we investigated the potential role of Shh signaling in renal interstitial fibrogenesis. Ureteral obstruction induced Shh, predominantly in the renal tubular epithelium of the fibrotic kidneys. Using Gli1(lacZ) knock-in mice, we identified renal interstitial fibroblasts as Shh-responding cells. In cultured renal fibroblasts, recombinant Shh protein activated Gli1 and induced α-smooth muscle actin (α-SMA), desmin, fibronectin, and collagen I expression, suggesting that Shh signaling promotes myofibroblast activation and matrix production. Blockade of Shh signaling with cyclopamine abolished the Shh-mediated induction of Gli1, Snail1, α-SMA, fibronectin, and collagen I. In vivo, the kidneys of Gli1-deficient mice were protected against the development of interstitial fibrosis after obstructive injury. In wild-type mice, cyclopamine did not affect renal Shh expression but did inhibit induction of Gli1, Snail1, and α-SMA. In addition, cyclopamine reduced matrix expression and mitigated fibrotic lesions. These results suggest that tubule-derived Shh mediates epithelial-mesenchymal communication by targeting interstitial fibroblasts after kidney injury. We conclude that Shh/Gli1 signaling plays a critical role in promoting fibroblast activation, production of extracellular matrix, and development of renal interstitial fibrosis.
Hong Ding; Dong Zhou; Sha Hao; Lili Zhou; Weichun He; Jing Nie; Fan Fan Hou; Youhua Liu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-02-02
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  23     ISSN:  1533-3450     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-01     Completed Date:  2012-06-25     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  801-13     Citation Subset:  IM    
Department of Pathology, University of Pittsburgh School of Medicine, PA 15261, USA.
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MeSH Terms
Actins / analysis
Cells, Cultured
Collagen Type I / biosynthesis
Epithelial-Mesenchymal Transition*
Fibroblasts / physiology
Hedgehog Proteins / genetics,  physiology*
Kidney / pathology*
Oncogene Proteins / genetics,  physiology
RNA, Messenger / analysis
Signal Transduction / physiology*
Trans-Activators / genetics,  physiology
Transcription Factors / genetics
Veratrum Alkaloids / pharmacology
Grant Support
Reg. No./Substance:
0/Actins; 0/Collagen Type I; 0/Gli protein; 0/Hedgehog Proteins; 0/Oncogene Proteins; 0/RNA, Messenger; 0/Trans-Activators; 0/Transcription Factors; 0/Veratrum Alkaloids; 0/alpha-smooth muscle actin, mouse; 0/snail family transcription factors; ZH658AJ192/cyclopamine

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