Asiatic acid from Cyclocarya paliurus regulates the autophagy-lysosome system via directly inhibiting TGF-β type I receptor and ameliorates diabetic nephropathy fibrosis.

Abstract

Diabetic nephropathy (DN) fibrosis is a major cause of end-stage renal disease with unsatisfactory therapy drugs and a low 5-year survival rate. There is a lack of specific and effective treatment drugs. In the present study, we report that asiatic acid (AA), a triterpenic acid found in Cyclocarya paliurus, has good anti-fibrosis activity both in vitro and in vivo. The STZ-induced diabetic model of rats was used to investigate the effects of AA on DN fibrosis. A 15-week AA treatment (10 mg kg-1 or 30 mg kg-1) markedly decreased urine albumin and blood urea nitrogen levels, and ameliorated increased mesangial matrix and glomerular fibrosis. HG + TGF-β1-induced HK-2 cells were applied to evaluate the anti-fibrosis effect of AA. The results revealed AA selectively blocked the interaction of TGF-β type I receptor (TGF-βRI) with Smad3 by binding to TGF-βRI, suppressed the subsequent phosphorylation and nuclear translocation of Smad3, and downregulated the major fibrotic protein expression of collagen I, fibronectin and a-smooth muscle actin (α-SMA), thereby switching the progress of epithelial-mesenchymal transition (EMT). Furthermore, the protein levels of LC3 and LAMP1 were significantly altered by AA administration, implying that the autophagy-lysosome system might be involved in DN fibrosis. However, the anti-fibrosis capacity of AA was partly counteracted by an autophagy-lysosome inhibitor (chloroquine). These findings indicate AA could decrease TGF-β1 secretion and suppress tubulointerstitial fibrosis by directly inhibiting TGF-βR1 and activating the autophagy-lysosome system. Altogether, AA may be a potential candidate drug for preventing DN fibrosis.