Aberrant DNA methylation of pregnane X receptor underlies metabolic gene alterations in the diabetic kidney

Published on Apr 1, 2018in American Journal of Physiology-renal Physiology3.144
· DOI :10.1152/AJPRENAL.00390.2017
Atsushi Watanabe6
Estimated H-index: 6
(National Defense Medical College),
Atsushi Watanabe4
Estimated H-index: 4
(National Defense Medical College)
+ 11 AuthorsToshiro Fujita121
Estimated H-index: 121
(UTokyo: University of Tokyo)
Sources
Abstract
Epigenetic abnormalities have been suggested to mediate metabolic memory observed in diabetic complications. We have shown that epigenetic alterations may induce persistent phenotypic changes in the proximal tubules of the diabetic kidneys. In this study, we show that pregnane X receptor (PXR), a xenobiotic nuclear receptor, is epigenetically altered and upregulated, and may have a possible function in the diabetic kidney. PXR has been shown to play a critical role in metabolic changes in obesity and diabetes; however, its distribution and function in the kidney are unknown. In the normal kidney, PXR was selectively expressed in the proximal tubular cells with demethylation in the promoter DNA. In db/db mice, significant increases in Pxr mRNA, further demethylation of DNA, and stimulatory histone marks in the promoter were observed. Epigenetic changes are likely to play a causative role in PXR induction since a DNA methyltransferase inhibitor increased PXR mRNA in cultured human proximal tubular cells. Administration of a PXR agonist increased mRNA levels of Slco2b1, a xenobiotic transporter, Rgc32, a molecule known to exert fibrotic effects in the kidney, and Pck1, a gluconeogenic enzyme, in the kidney. The expressions of these genes were inhibited by PXR siRNA in cultured proximal tubular cells. Increased mRNA levels of Slco2b1, Rgc32, and Pck1 were also observed in the kidney of db/db mice. These data indicate that PXR is upregulated in the diabetic kidney with aberrant epigenetic modifications and may modulate the course of diabetic kidney disease through the activation of these genes.
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