Journal
FASEB JOURNAL
Volume 27, Issue 10, Pages 4059-4075Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-231837
Keywords
HIF; cardiorenal anemia syndrome
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Funding
- Japan Society for the Promotion of Science [24390213, 22790781]
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [22790781, 24390213] Funding Source: KAKEN
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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-1 protein, but with functional impairment of the HIF-1 C-terminal transactivation domain (CTAD). Among factors that impeded the recruitment of transcriptional coactivators to the HIF-1CTAD, 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.Tanaka, T., Yamaguchi, J., Higashijima, Y., Nangaku, M. 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.
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