Hepatocyte Nuclear Factor-1? 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-?1, a profibrotic cytokine, induced dedifferentiation of cultured TECs, and the dedifferentiated TECs were re-epithelialized by the removal of TGF-?1 stimulation. In the re-epithelialization process, transcription factor hepatocyte nuclear factor 1, beta (HNF-1?) 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-?1 removal was abolished by HNF-1? knockdown. Furthermore, the ectopic expression of HNF-1? in the dedifferentiated TECs induced the re-epithelialization without the inhibition of TGF-?/Smad signaling, even in the presence of TGF-?1 stimulation. In mouse renal fibrosis model, unilateral ureteral obstruction model, HNF-1? expression in the TECs of the kidney was suppressed with fibrosis progression. Furthermore, the HNF-1? downregulated TECs resulted in dedifferentiation, which was characterized by expression of nestin. In conclusion, HNF-1? suppression in TECs is a crucial event for the dedifferentiation of TECs, and the upregulation of HNF-1? in TECs has a potential to restore the dedifferentiated TECs into their normal state, leading to the attenuation of renal fibrosis.

SUBMITTER: Omata M 

PROVIDER: S-EPMC4873210 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature