title: Expanding roles of the hypoxia-response network in chronic kidney disease.
abstract: Studies over the last two decades have established tubulointerstitial hypoxia as a final common pathway leading to end-stage kidney disease (ESKD). Chronic kidney disease (CKD) is frequently associated with various degrees of hypoxic injury in distinct tubular segments, depending on the etiology and pathological stages, which constitutes an intricate link among inflammation, oxidative stress and fibrosis. Resident cells in the kidney are equipped with mechanisms through which they cope with hypoxia. Here, transcription of genes by hypoxia-inducible factors (HIFs) plays a central role. In the ischemic kidney, HIF-1 is expressed in tubular and glomerular epithelial cells and in papillary interstitial cells, whereas HIF-2 is expressed in endothelial cells and interstitial fibroblasts. There is ample evidence that HIF protects the kidney from acute ischemic damage. In CKD, studies suggest that the function of HIF may be suppressed because of factors, such as oxidative stress and uremia, which may underlie the pathogenesis of both CKD and co-existing problems, such as renal anemia. Based on these observations, efforts are in progress to test whether restoration and activation of HIF might protect the kidney from CKD. Initial studies using non-specific or supraphysiological HIF activation suggested that the role of HIF may be multifactorial and depend on pathological context. On the other hand, specific HIF stabilizers, such as prolyl hydroxylase (PHD) inhibitors, are being developed for the treatment of renal anemia. Application of these compounds in experimental CKD may override those previous findings and provide deeper insight into the roles of hypoxia and oxygen-sensing pathways.
authors: 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: Tetsuhiro
authors: T
authors: Tanaka
mesh_terms: D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D010101:Oxygen Consumption; D064800:Prolyl-Hydroxylase Inhibitors / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D064800:Prolyl-Hydroxylase Inhibitors
keywords: Chronic kidney disease (CKD); Hypoxia; Hypoxia-inducible factor (HIF); Prolyl hydroxylase (PHD)