title: Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin.
abstract: We recently showed that imbalance of TGF-β/Smad signaling with over-activation of Smad3 but lower levels of Smad7 is a central mechanism of tissue fibrosis. In the present study, we report here that inhibition of Smad3 with naringenin (NG) and upregulation of Smad7 with asiatic acid (AA) produced an additive effect on inhibition of renal fibrosis in a mouse model of obstructive nephropathy. We found that AA, a triterpene from Centella Asiatica, functioned as a Smad7 agonist and suppressed TGF-β/Smad3-mediated renal fibrosis by inducing Smad7. Whereas, NG, a flavonoid from grapefruits and citrus fruits, was a Smad3 inhibitor that inhibited renal fibrosis by blocking Smad3 phosphorylation and transcription. The combination of AA and NG produced an additive effect on inhibition of renal fibrosis by blocking Smad3 while upregulating Smad7. Thus, rebalancing the disorder of TGF-β/Smad signaling by treatment with AA and NG may represent as a novel and effective therapy for chronic kidney disease associated with fibrosis.
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR.|School of Pharmacy, Anhui Medical University, An Hui, China.
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Meng
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR.|Department of Dermatology, Foshan Hospital of TCM, Foshan, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Medical University, An Hui, China.
authors.forename: Gui-ling
authors.initials: GL
authors.lastname: Ren
authors.affiliation: School of Pharmacy, Anhui Medical University, An Hui, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004359:Drug Therapy, Combination; D004965:Estrogen Antagonists / Q000494:pharmacology; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D044950:Flavanones / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007124:Immunoenzyme Techniques; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053978:Pentacyclic Triterpenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D044950:Flavanones; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C017032:asiatic acid; C005273:naringenin
keywords: Pathology Section; TGF-β/Smads; asiatic acid; naringenin; treatment for fibrosis