Journal
ONCOTARGET
Volume 6, Issue 35, Pages 36984-36997Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6100
Keywords
treatment for fibrosis; TGF-beta/Smads; asiatic acid; naringenin; Pathology section
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Funding
- Major State Basic Research Development Program of China (973 program) [2012CB517705]
- Research Grants Council of Hong Kong [GRF 468711, CUHK3/CRF/12R]
- Focused Investment Scheme A from Chinese University of Hong Kong
- National Natural Science Foundation of China [81300580, 81570623]
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We recently showed that imbalance of TGF-beta/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-beta/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-beta/Smad signaling by treatment with AA and NG may represent as a novel and effective therapy for chronic kidney disease associated with fibrosis.
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