RESUMO
Aristolochic acid nephropathy (AAN) is regarded as a kind of rapidly progressive renal fibrosis caused by the ingestion of herbal remedies containing aristolochic acids (AA). A mouse model of AAN was used to assess the patterns of renal injury and TGF-beta1/Smads signaling pathway during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis. A total of 28 mice were randomly assigned to four groups. Three groups were given aristolochic acid I (AAI) at different doses consecutively by gavage for 30 days, while the control group received only phosphate-buffered saline (PBS). Immunohistochemistry and semi-quantitative reverse transcriptase (RT-PCR) detection of the increased expression of fibroblast marker vimentin and de novo expression of alpha-smooth muscle actin (alpha-SMA) with the loss of epithelial maker cytokeratin 18 (CK18) can be utilized to assess AAI-induced tubular necrosis and extensive cortical interstitial fibrosis in a dose-dependent manner. Transforming growth factor-beta1 (TGF-beta1) has been widely recognized as a key fibrogenic cytokine. In our study, TGF-beta1 in the group at dose of 12 mg/kg/ day AAI increased 109.9% compared to control. Smad2 mRNA level in the group at dose of 4.2 mg/kg/day AAI increased 106.4%, and declined 12% in the group at dose of 12 mg/kg/day AAI; Smad4 expression was down-regulated in experimental groups, which declined 13% in the group at dose of 4.2 mg/kg/day AAI. Smad7 mRNA level was down-regulated by AAI in dose-dependence. Collectively, the involvement in interstitial fibrosis progression of active TGF-beta is highly suggested, via the Smads intracellular signaling pathway. These results may be attributed to the dosage of drug and the treatment of renal interstitial fibrosis.
