Tubular epithelial cell dedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1.
In the fibrotic kidney, tubular cells undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is characterized by sequential loss of epithelial markers and gain of mesenchymal features. For understanding of the molecular mechanism that governs this process, a high-throughput gene expression microarray analysis was used to identify the critical genes in the initial phase of the TGF-beta1-mediated EMT. Inhibitor of differentiation-1 (Id1), a dominant negative antagonist of the basic helix-loop-helix transcription factors, was found to be induced rapidly in human proximal tubular epithelial cells after TGF-beta1 treatment. This induction of Id1 depended on intracellular Smad signaling. Ectopic expression of Id1 suppressed epithelial E-cadherin and zonula occludens-1 expression. Id1 physically formed complex with basic helix-loop-helix transcription factor HEB (Hela E-box binding factor), sequestered its ability to bind to E-box, and repressed the trans-activation of E-cadherin promoter. However, overexpression of Id1 failed to induce alpha-smooth muscle actin, matrix metalloproteinase-2, fibronectin, and integrin-linked kinase (ILK), indicating its inability to confer a complete EMT. Overexpression of ILK or inhibition of ILK activity had no effect on Id1 induction by TGF-beta1, suggesting that Id1 and ILK have independent roles in epithelial dedifferentiation and EMT. In vivo, Id1 was induced exclusively in the degenerated, dilated renal tubular epithelium after unilateral ureteral obstruction. These studies identify Id1 transcriptional inhibitor as a crucial player in mediating cell dedifferentiation of renal tubular epithelium and suggest that EMT is a multistep process in which loss of epithelial adhesion does not necessarily lead to an autonomous mesenchymal transition.
Li
Yingjian
Y
Department of Pathology, University of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA. liuy@upmc.edu
Yang
Junwei
J
Luo
Jian-Hua
JH
Dedhar
Shoukat
S
Liu
Youhua
Y
D000328:Adult; D015820:Cadherins / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D016895:Culture Media, Serum-Free; D005786:Gene Expression Regulation; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics*; D007684:Kidney Tubules / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D018075:RNA, Complementary / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology; D019459:Urothelium / Q000166:cytology*
D015820:Cadherins; D016895:Culture Media, Serum-Free; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D018075:RNA, Complementary; D016212:Transforming Growth Factor beta