[Molecular mechanisms of tissue fibrosis]

Tissue fibrosis is a common cause of organ failure. Consequently, elucidation of the mechanisms underlying both the initiation and progression of fibrosis is an essential step toward establishing new therapeutic strategies for the treatment of organ failure. Fibroblasts are the principal effectors mediating fibrosis and their heterogeneous origins, including epithelial-mesenchymal transition (EMT), bone marrow-derived cell or fibrocyte, and endothelial-mesenchymal transition (EndMT), have been demonstrated. Chronic hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis. Recently, we reported that hypoxia induces EMT in renal tubular epithelial cells through activation of hypoxia-inducible factor-1alpha (HIF-1alpha). Using the Cre-loxP mediated gene targeting of HIF-1alpha or VHL which acts as a ubiquitin ligase to promote degradation of HIF-1alpha, we showed that HIF-1alpha plays a key role in the progression of renal fibrosis. As a large number of molecules that contribute to the induction of fibrosis have been identified, and their signal transduction pathway has been characterized, these fibrosis-related molecules have been proposed as therapeutic targets. EMT antagonists, TGF-beta signal modulator, and HIF-1alpha inhibitor could be useful for the treatment of fibrosis.