title: Fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation.
abstract: Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.forename: Chun-yan
authors.initials: CY
authors.lastname: Liu
authors.forename: Miao-miao
authors.initials: MM
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Wen-juan
authors.initials: WJ
authors.lastname: Mei
authors.forename: Wen-jun
authors.initials: WJ
authors.lastname: Yang
authors.forename: Yan-yun
authors.initials: YY
authors.lastname: Xie
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Zhang-zhe
authors.initials: ZZ
authors.lastname: Peng
authors.forename: Qiong-jing
authors.initials: QJ
authors.lastname: Yuan
authors.forename: Ji-shi
authors.initials: JS
authors.lastname: Liu
authors.forename: Gao-yun
authors.initials: GY
authors.lastname: Hu
authors.forename: Li-jian
authors.initials: LJ
authors.lastname: Tao
mesh_terms: D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007674:Kidney Diseases / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D011728:Pyridones; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse