GQ5 Hinders Renal Fibrosis in Obstructive Nephropathy by Selectively Inhibiting TGF-β-Induced Smad3 Phosphorylation.
TGF-β1, via Smad-dependent or Smad-independent signaling, has a central role in the pathogenesis of renal fibrosis. This pathway has been recognized as a potential target for antifibrotic therapy. Here, we identified GQ5, a small molecular phenolic compound isolated from the dried resin of Toxicodendron vernicifluum, as a potent and selective inhibitor of TGF-β1-induced Smad3 phosphorylation. In TGF-β1-stimulated renal tubular epithelial cells and interstitial fibroblast cells, GQ5 inhibited the interaction of Smad3 with TGF-β type I receptor (TβRI) by blocking binding of Smad3 to SARA, suppressed subsequent phosphorylation of Smad3, reduced nuclear translocation of Smad2, Smad3, and Smad4, and downregulated the transcription of major fibrotic genes such as α-smooth muscle actin (α-SMA), collagen I, and fibronectin. Notably, intraperitoneal administration of GQ5 in rats immediately after unilateral ureteral obstruction (UUO) selectively inhibited Smad3 phosphorylation in UUO kidneys, suppressed renal expression of α-SMA, collagen I, and fibronectin, and resulted in impressive renal protection after obstructive injury. Late administration of GQ5 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, our results suggest that GQ5 hinders renal fibrosis in rats by selective inhibition of TGF-β1-induced Smad3 phosphorylation.
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Jun
J
Ai
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Jing
J
Nie
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
Jiangbo
J
He
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Qin
Q
Guo
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Mei
M
Li
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Ying
Y
Lei
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Youhua
Y
Liu
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Zhanmei
Z
Zhou
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Fengxin
F
Zhu
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Min
M
Liang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China ffhouguangzhou@163.com yxcheng@mail.kib.ac.cn.
Yongxian
Y
Cheng
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and ffhouguangzhou@163.com yxcheng@mail.kib.ac.cn.
Fan Fan
FF
Hou
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002396:Catechols / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D009400:Nephrosclerosis / Q000378:metabolism / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy; D051900:Smad3 Protein / Q000378:metabolism*; D012251:Toxicodendron / Q000737:chemistry*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014517:Ureteral Obstruction
C000602390:3-(pentadec-8-enyl)catechol; D048868:Adaptor Proteins, Signal Transducing; D002396:Catechols; D004365:Drugs, Chinese Herbal; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C000602391:Zfyve9 protein, rat
GQ5; Smad3 phosphorylation; TGF-β1; fibrosis; obstructive nephropathy; renal