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Fasudil targets the RhoA/ROCK-NLRP3 axis to attenuate aristolochic acid-induced renal pyroptosis: translational
Mei-Zhu Gao1, Yan-Feng Zhou2, Zi-Yan Xu1
1Department of Nephrology and Traditional Chinese Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, China.
Abstract:
Aristolochic acid nephropathy (AAN), a progressive renal disease caused by exposure to Aristolochia-containing herbal products, remains a therapeutic challenge due to its complex phytotoxicity. This study aimed to elucidate the role of pyroptosis, a form of inflammatory cell death mediated by the NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways, in AAN pathogenesis and to evaluate the therapeutic potential of Fasudil, a RhoA/ROCK inhibitor. Using in vitro and in vivo models of AA-exposed NRK-52E cells and a murine AAN model, we investigated the activation of pyroptotic pathways and the effects of Fasudil. Western blot, ELISA, and immunofluorescence analyses revealed that AA exposure significantly upregulated NLRP3, caspase-1/3, and GSDMD/GSDME expression, leading to increased pyroptosis and inflammation. Fasudil treatment effectively suppressed RhoA/ROCK signaling, inhibited NLRP3 inflammasome activation, and attenuated pyroptosis, resulting in improved renal function and histopathology. Co-immunoprecipitation and molecular docking and molecular dynamics studies further demonstrated the interaction between RhoA/ROCK and NLRP3, providing mechanistic insights into Fasudil's therapeutic action. Additionally, near-infrared imaging using the caspase-3 probe 1-DPA2 enabled real-time, non-invasive monitoring of caspase-3 activation and therapeutic responses, highlighting the potential of molecular imaging as a diagnostic tool. Our findings demonstrate that Fasudil mitigates AAN by targeting dual pyroptotic pathways, offering a novel pharmacological strategy for managing this challenging disease. Furthermore, the integration of molecular imaging provides a translational approach for dynamic monitoring of renal injury and treatment efficacy. This study underscores the therapeutic potential of Fasudil and the clinical applicability of molecular imaging in AAN, paving the way for future research and therapeutic development.
