Treatment of renal fibrosis by rebalancing TGF-ß/Smad signaling with the combination of asiatic acid and naringenin.

ABSTRACT

We recently showed that imbalance of TGF-ß/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-ß/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-ß/Smad signaling by treatment with AA and NG may represent as a novel and effective therapy for chronic kidney disease associated with fibrosis.