ER stress triggers MCP-1 expression through SET7/9-induced histone methylation in the kidneys of db/db mice.
Epigenetics plays a key role in the pathogenesis of diabetic nephropathy (DN), although the precise regulatory mechanism is still unclear. Here, we examined the role of endoplasmic reticulum (ER) stress in histone H3 lysine 4 (H3K4) methyltransferase SET7/9-induced monocyte chemoattractant protein-1 (MCP-1) expression in the kidneys of db/db mice. Our results indicate that the expression of MCP-1 significantly increased in the kidneys of db/db mice in a time-dependent manner. An increased chromatin mark associated with an active gene (H3K4me1) at MCP-1 promoters accompanied this change in expression. The expression of SET7/9 and the recruitment to these promoters were also elevated. SET7/9 gene silencing with small interfering (si) RNAs significantly attenuated the expression of H3K4me1 and MCP-1. Furthermore, expression of signaling regulator glucose-regulated protein 78 (GRP78), a monitor of ER stress, significantly increased in the kidneys of db/db mice. The expression of spliced X-box binding protein 1 (XBP1s), an ER stress-inducible transcription factor, and recruitment to the SET7/9 promoters were also increased. XBP1s gene silencing with siRNAs significantly attenuated the expression of SET7/9, H3K4me1, and MCP-1. The chaperone betaine not only effectively downregulated the GRP78 and XBP1s expression levels but also markedly decreased the SET7/9, H3K4me1, and MCP-1 levels. Luciferase reporter assay demonstrated that XBP1s participated in ER stress-induced SET7/9 transcription, Taken together, these results reveal that ER stress can trigger the expression of MCP-1, in part through the XBP1s-mediated induction of SET7/9.
Dept. of Dept. of Nephrology, Xinqiao Hospital, The Third Military Medical Univ., 183 Xinqiao Main St., Shapingba District, Chongqing, People's Republic of China. fxb12@aliyun.com.
Jigang
J
Chen
Yanhong
Y
Guo
Wei
W
Zeng
Li
L
Huang
Qi
Q
Pang
Ling
L
Nie
Jiao
J
Mu
Fahuan
F
Yuan
Bing
B
Feng
D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000652:urine; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006360:Heat-Shock Proteins; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D000071717:X-Box Binding Protein 1
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D011495:Histone-Lysine N-Methyltransferase
ER stress; MCP-1; diabetic nephropathy; epigenetics