Serum response factor provokes epithelial-mesenchymal transition in renal tubular epithelial cells of diabetic nephropathy.
We investigated the role of serum response factor (SRF) in epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs) in diabetic nephropathy (DN). The expression of SRF, epithelial markers (E-cadherin and ZO-1), and mesenchymal markers (fibronectin, collagen-1, α-SMA, FSP-1) was examined in human proximal renal tubular epithelial cells (HK-2 cells) or renal medulla tissues following high glucose. SRF was upregulated by SRF plasmids and downregulated by CCG-1423 (a small molecule inhibitor of SRF) to investigate how SRF influenced EMT in TECs of DN. Streptozotocin was used to generate DM in rats. In HK-2 cells after high-glucose treatment and renal medulla tissues of diabetic rats, SRF, fibronectin, collagen-1, α-SMA, and FSP-1 increased, while E-cadherin and ZO-1 declined. SRF overexpression in HK-2 cells induced expression of Snail, an important transcription factor mediating EMT. Blockade of SRF by CCG-1423 reduced Snail induction and protected TECs from EMT both in vitro and in vivo. Together, increased SRF activity promotes EMT in TECs and dysfunction in DN. Targeting SRF by small molecule inhibitor may be an attractive therapeutic strategy for DN.
Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, People's Republic of China;
Long
L
Zhao
Department of Obstetrics, Shandong Wulian People's Hospital, Rizhao, People's Republic of China;
Lingzhen
L
Chi
Department of Nephrology, Shandong Weifang People's Hospital, Weifang, People's Republic of China; and.
Jun
J
Zhao
Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, People's Republic of China;
Xueling
X
Wang
Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, People's Republic of China;
Zhixin
Z
Chen
Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, People's Republic of China;
Linghang
L
Meng
Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, People's Republic of China;
Gang
G
Liu
Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, People's Republic of China; guangj@sdu.edu.cn.
Guangju
G
Guan
Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah.
Fei
F
Wang
D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D014157:Transcription Factors; C000620714:serum response factor, rat; D005947:Glucose
CCG-1423; HK-2 cells; Snail; diabetic nephropathy; epithelial-mesenchymal transition; renal tubular epithelial cells; serum response factor