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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
Author(s) -
Tanaka Tetsuhiro,
Yamaguchi Junna,
Higashijima Yoshiki,
Nangaku Masaomi
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-231837
Subject(s) - transactivation , hypoxia inducible factors , hypoxia (environmental) , gene expression , biology , gene , messenger rna , chemistry , microbiology and biotechnology , cancer research , biochemistry , organic chemistry , oxygen
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.— 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. FASEBJ. 27, 4059‐4075 (2013). www.fasebj.org