Epidermal growth factor receptor signaling mediates aldosterone-induced profibrotic responses in kidney.
Aldosterone has been recognized as a risk factor for the development of chronic kidney disease (CKD). Studies have indicated that enhanced activation of epidermal growth factor receptor (EGFR) is associated with the development and progression of renal fibrosis. But if EGFR is involved in aldosterone-induced renal fibrosis is less investigated. In the present study, we examined the effect of erlotinib, an inhibitor of EGFR tyrosine kinase activity, on the progression of aldosterone-induced renal profibrotic responses in a murine model underwent uninephrectomy. Erlotinib-treated rats exhibited relieved structural lesion comparing with rats treated with aldosterone alone, as characterized by glomerular hypertrophy, mesangial cell proliferation and expansion. Also, erlotinib inhibited the expression of TGF-β, α-SMA and mesangial matrix proteins such as collagen Ⅳ and fibronectin. In cultured mesangial cells, inhibition of EGFR also abrogated aldosterone-induced expression of extracellular matrix proteins, cell proliferation and migration. We also demonstrated that aldosterone induced the phosphorylation of EGFR through generation of ROS. And the activation of EGFR resulted in the phosphorylation of ERK1/2, leading to the activation of profibrotic pathways. Taken together, we concluded that aldosterone-mediated tissue fibrosis relies on ROS induced EGFR/ERK activation, highlighting EGFR as a potential therapeutic target for modulating renal fibrosis.
Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
Lili
L
Sheng
Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
Min
M
Yang
Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
Wei
W
Ding
Department of Nephrology, Shanghai Huashan Hospital, Fudan University, Shanghai 200240, China.
Minmin
M
Zhang
Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
Jianying
J
Niu
School of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China.
Zhongdong
Z
Qiao
Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China; Department of Nephrology, Shanghai Huashan Hospital, Fudan University, Shanghai 200240, China. Electronic address: yonggu@vip.163.com.
Yong
Y
Gu
D000450:Aldosterone / Q000009:adverse effects*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics
D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
Aldosterone; ERK1/2; Epidermal growth factor receptor; Profibrotic response; Reactive oxidative stress