Sustained increase of microRNA-21 abundance drives aristolochic acid-induced acute kidney injury to renal tubulointerstitial fibrosis

Objective To investigate the role of increased microRNA-21 (miR-21) in the development of renal tubulointerstitial fibrosis secondary to aristolochic acid induced acute kidney injury. Methods C57BL/6J male mice were intraperitoneally injected with aristolochic acid at a dose of 10 mg/kg. Blood samples and kidneys were harvested at day 1, 3, 7, 14, 28 after aristolochic acid treatment. To assess the role of miR-21 in aristolochic acid induced acute kidney injury to chronic kidney disease progression, mice were intravenously injected with anti-miR-21 or anti-scramble (10 mg/kg) at 1 h before aristolochic acid dosing, as well as d5 and d10 after aristolochic acid dosing. Results Increased serum creatinine and severe kidney injury were found at d3 after aristolochic acid treatment. Renal tubulointerstitial fibrosis was developed at d14 after aristolochic acid treatment. Protein expression of α-SMA, vimentin and collagen I were significantly up-regulated at d7 and peaked at d14 (P＜0.01), while protein abundance of E-Cadherin decreased at d14 and lasted until d28 (P＜0.01). The abundance of miR-21 increased at d7 after aristolochic acid dosing, peaking at d14 and thereafter maintaining at a high level. Anti-miR-21 intervention relieved renal injury with reduced serum creatinine (P＜0.05) and attenuation of renal tubulointerstitial fibrosis. Besides, the protein expression of α-SMA, vimentin, and collagen I/IV was all down-regulated after anti-miR-21 treatment (P＜0.05). PTEN was up-regulated and the ratio of its downstream genes p-AKT/AKT was decreased. (P＜0.05) Conclusions A single high dose of aristolochic acid leads to acute kidney injury and the development of renal tubulointerstitial fibrosis secondary to AKI. Renal tubulointerstitial fibrosis could be partially reversed by inhibiting miR-21 via PTEN/ p-AKT pathway.