title: Diabetes Induces Aberrant DNA Methylation in the Proximal Tubules of the Kidney.
abstract: 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, a marker of diabetic kidney disease, was accompanied by histone modification changes. Furthermore, inhibition of DNA methyltransferase 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.
authors: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, CREST, Japan Science and Technology Agency, Tokyo, Japan;
authors: Takeshi
authors: T
authors: Marumo
authors: Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, and.
authors: Shintaro
authors: S
authors: Yagi
authors: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology.
authors: Wakako
authors: W
authors: Kawarazaki
authors: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology.
authors: Mitsuhiro
authors: M
authors: Nishimoto
authors: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology.
authors: Nobuhiro
authors: N
authors: Ayuzawa
authors: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology.
authors: Atsushi
authors: A
authors: Watanabe
authors: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology.
authors: Kohei
authors: K
authors: Ueda
authors: Apheresis and Dialysis Center, School of Medicine, Keio University, Tokyo, Japan; and.
authors: Junichi
authors: J
authors: Hirahashi
authors: Department of Advanced Nephrology and Regenerative Medicine, The University of Tokyo, Tokyo, Japan;
authors: Keiichi
authors: K
authors: Hishikawa
authors: Department of Pharmacology, School of Medicine, Kyorin University, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Sakurai
authors: Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, and.
authors: Kunio
authors: K
authors: Shiota
authors: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, CREST, Japan Science and Technology Agency, Tokyo, Japan; Toshiro.FUJITA@rcast.u-tokyo.ac.jp tmarumo-npr@umin.ac.jp.
authors: Toshiro
authors: T
authors: Fujita
mesh_terms: D000818:Animals; D019175:DNA Methylation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
keywords: angiotensin; diabetes; renal proximal tubule cell
references: Comp Hepatol. 2012 Apr 23;11(1):1
references: 22524730
references: J Clin Invest. 2006 Jun;116(6):1696-702
references: 16691295
references: Diabetes. 2012 Oct;61(10):2597-608
references: 22664958
references: Cell Rep. 2013 Apr 25;3(4):1020-7
references: 23583180
references: Kidney Int. 2010 Sep;78(6):569-77
references: 20555317
references: Nature. 2014 Jun 26;510(7506):537-41
references: 24847876
references: Diabetes. 2006 Oct;55(10):2747-56
references: 17003339
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5211-6
references: 11320253
references: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7004-11
references: 11416179
references: Am J Hypertens. 2012 Jun;25(6):684-9
references: 22378037
references: Kidney Int Suppl. 2011 Mar;(120):S1-6
references: 21358696
references: Am J Physiol Renal Physiol. 2011 Feb;300(2):F301-10
references: 21147843
references: Cell. 2013 Mar 28;153(1):56-69
references: 23540690
references: Cell Metab. 2009 Sep;10(3):189-98
references: 19723495
references: Pharmacol Rev. 2007 Sep;59(3):251-87
references: 17878513
references: Trends Cell Biol. 2013 May;23(5):203-9
references: 23277089
references: Genome Res. 2008 Dec;18(12):1969-78
references: 18971312
references: Kidney Int. 2014 May;85(5):1009-11
references: 24786873
references: Trends Endocrinol Metab. 2013 Jun;24(6):301-9
references: 23647930
references: Nat Rev Endocrinol. 2010 Dec;6(12):665-75
references: 21045787
references: Diabetes. 2004 Apr;53(4):1119-27
references: 15047630
references: Biochem Biophys Res Commun. 2013 Mar 29;433(1):66-72
references: 23454124
references: EMBO J. 2012 Mar 21;31(6):1405-26
references: 22293752
references: J Clin Invest. 2013 May;123(5):1934-6
references: 23619355
references: J Clin Endocrinol Metab. 2012 Oct;97(10):E2026-30
references: 22802087
references: Diabetes. 2004 Mar;53(3):784-94
references: 14988265
references: Annu Rev Physiol. 2012;74:351-75
references: 22335797
references: Genome Biol. 2013;14(10):R108
references: 24098934
references: N Engl J Med. 2008 Oct 9;359(15):1577-89
references: 18784090
references: Nat Med. 2013 Nov;19(11):1496-504
references: 24141423
references: Nature. 2013 Aug 22;500(7463):477-81
references: 23925113
references: N Engl J Med. 2014 Apr 17;370(16):1514-23
references: 24738668
references: J Biol Chem. 2006 Jan 13;281(2):1008-15
references: 16278214
references: J Am Soc Nephrol. 2005 Jan;16(1):27-45
references: 15563560
references: Nucl Recept. 2003 Aug 8;1(1):5
references: 12952540
references: J Am Soc Nephrol. 2007 Jan;18(1):37-45
references: 17135398
references: J Am Soc Nephrol. 2012 Jul;23(7):1181-9
references: 22518004
references: Kidney Int. 1999 Sep;56(3):1022-8
references: 10469370
references: J Clin Invest. 2008 Aug;118(8):2747-57
references: 18636120
references: Cell Metab. 2013 Aug 6;18(2):296-302
references: 23931760
references: BMC Immunol. 2012;13:58
references: 23116172