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Aristolochic acid I promotes renal tubulointerstitial fibrosis by activating the mannan-binding lectin serine
Chen Wang1, Hong Zhang1, Jiahe Wang1
1Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Abstract:
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.
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