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Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB

Dilinaer Bolati1, Hidehisa Shimizu, Maimaiti Yisireyili

  • 1Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan.

BMC Nephrology
|March 19, 2013
PubMed
Abstract

Insights

Indoxyl sulfate lowers Nrf2 expression in chronic kidney disease (CKD) by activating NF-κB. AST-120, an oral sorbent, reverses this by reducing indoxyl sulfate, thus upregulating Nrf2 and decreasing oxidative stress in CKD rats.

Area of Science:

  • Nephrology
  • Toxicology
  • Molecular Biology

Background:

  • Indoxyl sulfate accumulates in chronic kidney disease (CKD), accelerating disease progression.
  • Nrf2 expression and related genes are downregulated in CKD kidneys.
  • AST-120 reduces serum indoxyl sulfate and slows CKD progression.

Purpose of the Study:

  • To investigate if indoxyl sulfate downregulates Nrf2 in human proximal tubular cells and rat kidneys.
  • To determine if AST-120 upregulates Nrf2 in CKD rat kidneys.

Main Methods:

  • Indoxyl sulfate's effect on Nrf2 expression was studied in HK-2 cells and four groups of rats (DN, DN+IS, DH, DH+IS).
  • AST-120 was administered to subtotally nephrectomized CKD rats to assess its impact on Nrf2 expression.

Main Results:

  • Indoxyl sulfate decreased Nrf2 expression in HK-2 cells, an effect mitigated by NF-κB inhibitors.
  • CKD rats showed reduced renal Nrf2, HO-1, and NQO1 expression, and increased 8-OHdG.
  • AST-120 increased renal Nrf2, HO-1, and NQO1 expression, while decreasing 8-OHdG in CKD rats.

Conclusions:

  • Indoxyl sulfate downregulates renal Nrf2 via NF-κB activation, leading to decreased HO-1/NQO1 and increased ROS.
  • AST-120 upregulates renal Nrf2 in CKD rats by reducing indoxyl sulfate, thereby increasing HO-1/NQO1 and reducing ROS.

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