title: Hepatocyte Nuclear Factor-1β Induces Redifferentiation of Dedifferentiated Tubular Epithelial Cells.
abstract: Tubular epithelial cells (TECs) can be dedifferentiated by repetitive insults, which activate scar-producing cells generated from interstitial cells such as fibroblasts, leading to the accumulation and deposition of extracellular matrix molecules. The dedifferentiated TECs play a crucial role in the development of renal fibrosis. Therefore, renal fibrosis may be attenuated if dedifferentiated TECs are converted back to their normal state (re-epithelialization). However, the mechanism underlying the re-epithelialization remains to be elucidated. In the present study, TGF-β1, a profibrotic cytokine, induced dedifferentiation of cultured TECs, and the dedifferentiated TECs were re-epithelialized by the removal of TGF-β1 stimulation. In the re-epithelialization process, transcription factor hepatocyte nuclear factor 1, beta (HNF-1β) was identified as a candidate molecule involved in inducing re-epithelialization by means of DNA microarray and biological network analysis. In functional validation studies, the re-epithelialization by TGF-β1 removal was abolished by HNF-1β knockdown. Furthermore, the ectopic expression of HNF-1β in the dedifferentiated TECs induced the re-epithelialization without the inhibition of TGF-β/Smad signaling, even in the presence of TGF-β1 stimulation. In mouse renal fibrosis model, unilateral ureteral obstruction model, HNF-1β expression in the TECs of the kidney was suppressed with fibrosis progression. Furthermore, the HNF-1β downregulated TECs resulted in dedifferentiation, which was characterized by expression of nestin. In conclusion, HNF-1β suppression in TECs is a crucial event for the dedifferentiation of TECs, and the upregulation of HNF-1β in TECs has a potential to restore the dedifferentiated TECs into their normal state, leading to the attenuation of renal fibrosis.
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Omata
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Doke
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Chikaomi
authors.initials: C
authors.lastname: Yamada
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kawashima
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Sho
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Enomoto
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Furuya
authors.affiliation: Asubio Pharma Co., Ltd., Kobe, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Inomata
mesh_terms: D000256:Adenoviridae; D000818:Animals; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D020869:Gene Expression Profiling; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; C496495:HNF1B protein, human; C496496:Hnf1b protein, mouse; D034741:RNA, Small Interfering; D051785:Smad Proteins; D051539:Hepatocyte Nuclear Factor 1-beta