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Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase

Chiao-Yin Sun1, Shih-Chung Chang, Mai-Szu Wu

  • 1School of Medicine, Chang Gung University, Taoyuan, Taiwan.

Kidney International
|January 13, 2012
PubMed

Insights

Uremic toxins like indoxyl sulfate and p-cresyl sulfate decrease the renoprotective Klotho gene expression by causing DNA hypermethylation. This epigenetic modification in the kidneys suggests a new mechanism in uremia-related diseases.

Area of Science:

  • Nephrology
  • Epigenetics
  • Molecular Biology

Background:

  • Klotho, a renoprotective and antiaging gene, shows reduced expression in uremia.
  • Klotho may function as a tumor suppressor, with its expression potentially repressed by DNA hypermethylation in cancer.

Purpose of the Study:

  • To investigate how uremic toxins regulate Klotho gene expression in a mouse model of uremia.
  • To explore the role of DNA hypermethylation and DNA methyltransferases in Klotho gene repression by uremic toxins.

Main Methods:

  • Uninephrectomized B-6 mice were administered indoxyl sulfate or p-cresyl sulfate.
  • Cultured human renal tubular HK2 cells were used as an in vitro model and treated with these toxins.
  • DNA methylation, Klotho expression, and DNA methyltransferase (DNMT) expression levels were analyzed.
  • The effect of DNMT inhibition using 5-aza-2'-deoxycytidine was assessed.

Main Results:

  • Uremic toxins increased serum concentrations, kidney fibrosis, Klotho gene CpG hypermethylation, and decreased Klotho expression in mouse kidneys.
  • Indoxyl sulfate and p-cresyl sulfate significantly increased DNMT 1, 3a, and 3b expression in HK2 cells.
  • Inhibition of DNMT1 by 5-aza-2'-deoxycytidine led to Klotho gene demethylation and increased Klotho expression in vitro.

Conclusions:

  • Uremic toxins inhibit Klotho gene expression through DNA hypermethylation, indicating an epigenetic mechanism.
  • Epigenetic modification of genes by uremic toxins may be a critical pathological pathway in kidney disease.

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