Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro-inflammatory factors in vivo and in vitro.
OBJECTIVE
Renal fibrosis acts as the common pathway leading to the development of end-stage renal disease. The present study investigated, in vivo and in vitro, the anti-fibrotic and anti-inflammatory effects, particularly on the epithelial to mesenchymal transition of renal tubular cells, exerted by honokiol, a phytochemical used in traditional medicine, and mechanisms underlying these effects.


METHODS
Anti-fibrotic effects in vivo were assayed in a rat model of renal fibrosis [the unilateral ureteral obstruction (UUO) model]. A rat tubular epithelial cell line (NRK-52E) was stimulated by transforming growth factor-β1 (TGF-β1) and treated with honokiol to explore possible mechanisms of these anti-fibrotic effects. Gene or protein expression was analysed by Northern or Western blotting. Transcriptional regulation was investigated using luciferase activity driven by a connective tissue growth factor (CTGF) promoter.


RESULTS
Honokiol slowed development of renal fibrosis both in vivo and in vitro. Honokiol treatment attenuated tubulointerstitial fibrosis and expression of pro-fibrotic factors in the UUO model. Honokiol also decreased expression of the mRNA for the chemokine CCL2 and for the intracellular adhesion molecule-1, as well as accumulation of type I (α1) collagen and fibronectin in UUO kidneys. Phosphorylation of Smad-2/3 induced by TGF-β1 and CTGF luciferase activity in renal tubular cells were also inhibited by honokiol.


CONCLUSIONS
Honokiol suppressed expression of pro-fibrotic and pro-inflammatory factors and of extracellular matrix proteins. Honokiol may become a therapeutic agent to prevent renal fibrosis.
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. ckchiang@ntu.edu.tw
Chih-Kang
CK
Chiang
Meei-Ling
ML
Sheu
Yi-Wei
YW
Lin
Cheng-Tien
CT
Wu
Chin-Ching
CC
Yang
Min-Wei
MW
Chen
Kuan-Yu
KY
Hung
Kuan-Dun
KD
Wu
Shing-Hwa
SH
Liu
D000199:Actins / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D017930:Genes, Reporter; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D017705:Lignans / Q000494:pharmacology / Q000627:therapeutic use*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000473:pathology; D000498:Allyl Compounds; D010636:Phenols
D000199:Actins; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D055513:Connective Tissue Growth Factor; D016326:Extracellular Matrix Proteins; D018799:Intercellular Adhesion Molecule-1; D017705:Lignans; D008156:Luciferases; D012333:RNA, Messenger; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
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