Diabetes induces aberrant DNA methylation in the proximal tubules of the kidney

Takeshi Marumo*, Shintaro Yagi, Wakako Kawarazaki, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Atsushi Watanabe, Kohei Ueda, Junichi Hirahashi, Keiichi Hishikawa, Hiroyuki Sakurai, Kunio Shiota, Toshiro Fujita

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Citations (Scopus)


Epigenetic mechanisms may underlie the progression of diabetic kidney disease. Because the kidney is a heterogeneous organ with different cell types, we investigated DNA methylation status of the kidney in a cell type-specific manner. We first identified genes specifically demethylated in the normal proximal tubules obtained from control db/m mice, and next delineated the candidate disease-modifying genes bearing aberrant DNA methylation induced by diabetes using db/db mice. Genes involved in glucose metabolism, including Sglt2, Pck1, and G6pc, were selectively hypomethylated in the proximal tubules in control mice. Hnf4a, a transcription factor regulating transporters for reabsorption, was also selectively demethylated. In diabetic mice, aberrant hypomethylation of Agt, Abcc4, Cyp4a10, Glut5, and Met and hypermethylation of Kif20b, Cldn18, and Slco1a1 were observed. Time-dependent demethylation of Agt, amarker of diabetic kidney disease, was accompanied by histonemodification changes. Furthermore, inhibition ofDNAmethyltransferase or histone deacetylase increased Agt mRNA in cultured human proximal tubular cells. Aberrant DNA methylation and concomitant changes in histone modifications and mRNA expression in the diabetic kidney were resistant to antidiabetic treatment with pioglitazone. These results suggest that an epigenetic switch involving aberrant DNA methylation causes persistent mRNA expression of select genes that may lead to phenotype changes of the proximal tubules in diabetic kidney disease.

Original languageEnglish
Pages (from-to)2388-2397
Number of pages10
JournalJournal of the American Society of Nephrology
Issue number10
Publication statusPublished - 2015 Oct 1
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology


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