Sonic hedgehog signaling mediates epithelial-mesenchymal communication and promotes renal fibrosis.
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.
Department of Pathology, University of Pittsburgh School of Medicine, PA 15261, USA.
Hong
H
Ding
Dong
D
Zhou
Sha
S
Hao
Lili
L
Zhou
Weichun
W
He
Jing
J
Nie
Fan Fan
FF
Hou
Youhua
Y
Liu
D000199:Actins / Q000032:analysis; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
D000199:Actins; D024042:Collagen Type I; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; C000604429:Snai1 protein, mouse; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C544013:alpha-smooth muscle actin, mouse; C000541:cyclopamine