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

FASEB J. 2013 Oct;27(10):4059-75. doi: 10.1096/fj.13-231837. Epub 2013 Jun 21.


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.

Keywords: HIF; cardiorenal anemia syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Humans
  • Hypoxia-Inducible Factor 1 / genetics
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Indican / pharmacology*
  • Mice
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Rats
  • Renal Insufficiency, Chronic / metabolism*
  • Signal Transduction / physiology
  • Uremia / metabolism*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*


  • Hypoxia-Inducible Factor 1
  • RNA, Messenger
  • p300-CBP Transcription Factors
  • Extracellular Signal-Regulated MAP Kinases
  • Indican