title: A mechanistic link between renal ischemia and fibrosis.
abstract: Renal fibrosis is characterized by tubular cell atrophy and accumulation of extracellular matrix. Fibroblast activation becomes evident in areas surrounding atrophic tubules, with rarefaction of peritubular capillaries. Tubulointerstitial hypoxia is the final common pathway in progressive kidney disease. Hypoxia suppresses tubular epithelial growth and leads to failure of remodeling by facilitating dedifferentiation and apoptosis. Profibrotic factors such as transforming growth factor-β (TGF-β) mediate fibroblast activation, and recruited leukocytes, which appear in hypoxic areas, contribute to fibrosis. While resident renal cells adapt to the hypoxic environment via upregulation of relevant genes by hypoxia-inducible factor (HIF) family members, hypoxic adaptation via HIF may not be sufficient in chronic kidney disease (CKD) due to multiple factors. Thus, restoration of HIF-mediated responses may contribute to amelioration of CKD pathology. Studies to date have reported that HIF activation reduces inflammation and oxidative stress and ameliorates injury by decreasing tubular cell apoptosis and restoring peritubular capillary network. Prolyl hydroxylase domain (PHD) inhibitors that specifically activate HIF are currently evaluated for the treatment of renal anemia and may be effective for the treatment of CKD.
authors.affiliation: Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. tetsu-tky@umin.ac.jp.
authors.forename: Tetsuhiro
authors.identifier: http://orcid.org/0000-0002-2238-4215
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D005355:Fibrosis; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007511:Ischemia / Q000473:pathology*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology*; D008954:Models, Biological; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: Fibrosis; Hypoxia; Hypoxia-inducible factor (HIF); Prolyl hydroxylase domain-containing protein (PHD)