DNA methyltransferase 1 may be a therapy target for attenuating diabetic nephropathy and podocyte injury.
The contribution of DNA methylation to diabetic nephropathy, especially the effect on podocyte integrity, is not clarified. Here we found that albuminuria in a db/db mouse model was markedly attenuated after treatment with a DNA methylation inhibitor. This was accompanied by alleviation of glomerular hypertrophy, mesangial matrix expansion, and podocyte injury. The expression of DNA methyltransferase 1 (Dnmt1), nuclear factor Sp1, and nuclear factor kappa B (NFκB)-p65 markedly increased in podocytes in vivo and in vitro under the diabetic state. The increased expression of Dnmt1 was attenuated after treatment with 5-azacytidine or 5-aza-2'-deoxycytidine or Dnmt1 knockdown, accompanied by restored decreased podocyte slit diaphragm proteins resulting from hypermethylation and improved podocyte motility. Further studies found that increased Sp1 and NFκB-p65 interacted in the nucleus of podocytes incubated with high glucose, and Sp1 bound to the Dnmt1 promoter region. The involvement of the Sp1/NFκB-p65 complex in Dnmt1 regulation was confirmed by the observation that Sp1 knockdown using mithramycin A or siRNA decreased Dnmt1 protein levels. The luciferase reporter assay further indicated that Dnmt1 was a direct target of Sp1. Thus, inhibition of DNA methylation may be a new therapeutic avenue for treating diabetic nephropathy. Hence, the Sp1/NFκB p65-Dnmt1 pathway may be exploited as a therapeutic target for protecting against podocyte injury in diabetic nephropathy.
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Li
L
Zhang
Southern Medical University, Guangzhou, China.
Qianmei
Q
Zhang
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Shuangxin
S
Liu
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Yuanhan
Y
Chen
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Ruizhao
R
Li
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Ting
T
Lin
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Chunping
C
Yu
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Hong
H
Zhang
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Zhongshun
Z
Huang
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Southern Medical University, Guangzhou, China.
Xinchen
X
Zhao
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Xiaofan
X
Tan
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Zhuo
Z
Li
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Zhiming
Z
Ye
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Jianchao
J
Ma
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Bin
B
Zhang
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Wenjian
W
Wang
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: shiweigd139@163.com.
Wei
W
Shi
Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: xinlingliang_ggh@163.com.
Xinling
X
Liang
D000419:Albuminuria / Q000201:enzymology / Q000517:prevention & control; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection
D004791:Enzyme Inhibitors; C498144:Rela protein, mouse; D016329:Sp1 Transcription Factor; D051996:Transcription Factor RelA; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619381:Dnmt1 protein, mouse; D001374:Azacitidine
5-azacytidine; DNA methylation inhibitor; diabetic db/db mice; diabetic nephropathy; podocyte