title: Indoxyl sulfate signals for rapid mRNA stabilization of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) and suppresses the expression of hypoxia-inducible genes in experimental CKD and uremia.
abstract: Chronic hypoxia in the tubulointerstitium serves as a final common pathway in progressive renal disease. Circumstantial evidence suggests that hypoxia-inducible factor (HIF)-1 in the ischemic tubules may be functionally inhibited in a chronic kidney disease (CKD) milieu. In this study, we hypothesized that indoxyl sulfate (IS), a uremic toxin, impairs the cellular hypoxic response. In human kidney (HK-2) proximal tubular cells, IS reduced the hypoxic induction of HIF-1 target genes. This effect was not associated with quantitative changes in the HIF-1α protein, but with functional impairment of the HIF-1α C-terminal transactivation domain (CTAD). Among factors that impeded the recruitment of transcriptional coactivators to the HIF-1αCTAD, IS markedly up-regulated Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) through a mechanism of post-transcriptional mRNA stabilization involving the extracellular signal-regulated kinase (ERK) 1/2 pathway. In vivo, disproportionate expression of HIF target genes was demonstrated in several CKD models, which was offset by an oral adsorbent, AST-120. Furthermore, administration of indole reduced the induction of angiogenic, hypoxia-inducible genes in rats with experimental heart failure. Results of these studies reveal a novel role of IS in modulating the transcriptional response of HIF-1 and provide insight into molecular mechanisms underlying progressive nephropathies as well as cardiovascular complications.
authors.affiliation: 1Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, 113-8655 Tokyo, Japan. T.T., tetsu-tky@umin.ac.jp.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Junna
authors.initials: J
authors.lastname: Yamaguchi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Higashijima
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D007200:Indican / Q000494:pharmacology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014511:Uremia / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D050880:p300-CBP Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D007200:Indican
keywords: HIF; cardiorenal anemia syndrome