期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 314, 期 4, 页码 F551-F560出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00390.2017
关键词
diabetic kidney disease; DNA methylation; epigenetics; pregnane X receptor; proximal tubules
资金
- AMED-CREST
- Cardiovascular Diseases and Diabetes Mellitus from the Japan Agency for Medical Research and Development, AMED [JP17ek0210093]
- JSPS KAKENHI [25461230, 15H05788, 16K15466]
- Practical Research Project for Life-Style related Diseases
- Grants-in-Aid for Scientific Research [17K16074, 25461230, 16K15494, 15H05788, 15K08987, 15K19443, 16K15466] Funding Source: KAKEN
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 solute carrier organic anion transporter family member 2B1 (Slco2b1), a xenobiotic transporter: response gene to complement 32 (Rgc32). a molecule known to exert fibrotic effects in the kidney; and phosphoenolpyruvate carboxykinase 1 (Pck1), a gluconeogenic enzyme in the kidney. The expressions of these genes were inhibited by PXR small interfering RNA in cultured proximal tubular cells. Increased mRNA levels of Slco2bl, 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据