Transcription Factor Egr1 is Involved in High Glucose-Induced Proliferation and Fibrosis in Rat Glomerular Mesangial Cells.
Backgroud: Diabetic nephropathy is one of the most frequent causes of end-stage renal disease and is associated with proliferation of glomerular mesangial cells (MCs) and excessive production of the extracellular matrix (ECM). Several studies have shown that early growth response factor 1 (Egr1) plays a key role in renal fibrosis by regulating the expression of genes encoding ECM components. However, whether Egr1 also contributes to diabetic nephropathy is unclear.


METHODS
In the present study, we compared the expression of Egr1 in kidneys from OLETF rats with spontaneous type 2 diabetes and healthy LETO rats. We also examined whether high glucose and TGF-β1 signaling up-regulated Egr1 expression in cultured MCs, and whether Egr1 expression influenced MC proliferation and expression of ECM genes.


RESULTS
We found that higher expression of Egr1 and TGF-β1, at both the mRNA and protein levels, the kidneys from OLETF rats vs. LETO rats. High glucose or TGF-β1 signaling rapidly up-regulated expression of Egr1 mRNA and protein in cultured MCs. Overexpressing Egr1 in MCs by transfection with M61-Egr1 plasmid or treatment with high glucose up-regulated expression of fibronectin, type IV collagen and TGF-β1, and promoted MC proliferation. Conversely, siRNA-mediated silencing of Egr1 expression down-regulated these genes and inhibited MC proliferation. Chromatin immunoprecipitation (ChIP) assays revealed that Egr1 bound to the TGF-β1 promoter.


CONCLUSIONS
Our results provide strong evidence that Egr1 contributes to diabetic nephropathy by enhancing MC proliferation and ECM production, in part by interacting with TGF-β1.
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Dan
D
Wang
Mei-Ping
MP
Guan
Zong-Ji
ZJ
Zheng
Wen-Qi
WQ
Li
Fu-Ping
FP
Lyv
Ruo-Yu
RY
Pang
Yao-Ming
YM
Xue
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D024141:Collagen Type IV / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000473:pathology*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D020334:Rats, Inbred OLETF; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
D024141:Collagen Type IV; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D005353:Fibronectins; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D005947:Glucose