Hepatocyte Nuclear Factor-1β Induces Redifferentiation of Dedifferentiated Tubular Epithelial Cells

• Published in: PloS one 2016-05, Vol.11 (5), p.e0154912-e0154912
• Main Authors: Omata, Mitsugu, Doke, Yukiko, Yamada, Chikaomi, Kawashima, Kayoko, Sho, Rumiko, Enomoto, Kei, Furuya, Mayumi, Inomata, Norio
• Format: Article
• Language: English
• Subjects: Adenoviridae; Animals; Biology and Life Sciences; Cell cycle; Cell Dedifferentiation; Cell Differentiation; Collagen; Cytokines - metabolism; Deoxyribonucleic acid; Diabetes; DNA; DNA microarrays; Ectopic expression; Epithelial cells; Epithelial Cells - cytology; Extracellular matrix; Female; Fibroblasts; Fibrosis; Fibrosis - metabolism; Gene expression; Gene Expression Profiling; Hepatocyte nuclear factor 1; Hepatocyte Nuclear Factor 1-beta - metabolism; Humans; Immunohistochemistry; Interstitial cells; Kidney - pathology; Kidney diseases; Kidney Tubules - cytology; Kidneys; Medicine and Health Sciences; Mice; Mice, Inbred ICR; Mutation; Nestin; Network analysis; Oligonucleotide Array Sequence Analysis; Phosphorylation; Real-Time Polymerase Chain Reaction; Research and Analysis Methods; RNA, Small Interfering - metabolism; Rodents; Scars; Signaling; Smad protein; Smad Proteins - metabolism; Stimulation; Transforming growth factor-b1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154912

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.