Aristolochic acid I promotes renal tubulointerstitial fibrosis by activating the mannan-binding lectin serine protease 1-complement system

Aristolochic acid I (AAI) activates the Complement System, triggering inflammation and renal interstitial fibrosis (RIF). This study investigated the role of mannan-binding lectin serine Protease 1 (MASP1) in AAI-induced RIF. Treating human proximal tubular (HK-2) cells with AAI (2.5, 5, 10 μM) increased inflammatory factors, fibrosis proteins, complement factor C3a, and MASP1/MASP2 expression. Similar increases occurred in AAI-treated (5 mg/kg) C57BL/6J mice. Inhibiting MASP1 using siRNA (siMASP1) or an inhibitor (C1INH, 100 μg/mL) in HK-2 cells reduced AAI-induced C3a elevation, complement activation, inflammation, MASP2, and fibrosis proteins. Correspondingly, in situ renal inhibition of MASP1 in mice using adeno-associated virus 9 (AAV9-siMASP1) suppressed complement activation, kidney inflammation, and RIF following AAI exposure. These results demonstrate that AAI promotes RIF by activating the MASP1-complement pathway, leading to C3a release and inflammation. This study elucidates a mechanism for AAI-induced RIF and suggests MASP1 inhibition as a potential therapeutic strategy against AAI toxicity.