Legumain is required for maintenance of normal kidney homeostasis. However, its role in acute kidney injury (AKI) is still unclear. Here, we induced AKI by bilateral ischemia-reperfusion injury (IRI) of renal arteries or folic acid in lgmnWT and lgmnKO mice. We assessed serum creatinine, blood urea nitrogen, histological indexes of tubular injury, and expression of KIM-1 and NGAL. Inflammatory infiltration was evaluated by immunohistological staining of CD3 and F4/80, and expression of TNF-α, CCL-2, IL-33, and IL-1α. Ferroptosis was evaluated by Acsl4, Cox-2, reactive oxygen species (ROS) indexes H2DCFDA and DHE, MDA and glutathione peroxidase 4 (GPX4). We induced ferroptosis by hypoxia or erastin in primary mouse renal tubular epithelial cells (mRTECs). Cellular survival, Acsl4, Cox-2, LDH release, ROS, and MDA levels were measured. We analyzed the degradation of GPX4 through inhibition of proteasomes or autophagy. Lysosomal GPX4 was assessed to determine GPX4 degradation pathway. Immunoprecipitation (IP) was used to determine the interactions between legumain, GPX4, HSC70, and HSP90. For tentative treatment, RR-11a was administrated intraperitoneally to a mouse model of IRI-induced AKI. Our results showed that legumain deficiency attenuated acute tubular injury, inflammation, and ferroptosis in either IRI or folic acid-induced AKI model. Ferroptosis induced by hypoxia or erastin was dampened in lgmnKO mRTECs compared with lgmnWT control. Deficiency of legumain prevented chaperone-mediated autophagy of GPX4. Results of IP suggested interactions between legumain, HSC70, HSP90, and GPX4. Administration of RR-11a ameliorated ferroptosis and renal injury in the AKI model. Together, our data indicate that legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in AKI.

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ObjectiveTo investigate whether methadone maintenance treatment (MMT) is correlated with sexual dysfunction in heroin-dependent men and to determine the prevalence and risk factors of sexual dysfunction among men on MMT.MethodsThe study included a retrospective survey and a cross-sectional survey which contained interviews of 293 men who are currently engaged in MMT. The results of the two surveys were compared. For a subset of 43 participants, radioimmunoassay was additionally conducted using retrospective and prospective blood samples to test the levels of plasma testosterone and luteinizing hormone. Other study evaluations were the International Index of Erectile Function (IIEF-15), and Self-rating Depression Scale.ResultsSexual dysfunction in all five IIEF-15 domains (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) was strongly associated with long-term use of heroin. A decrease in the severity of sexual dysfunction was associated with MMT initiation. Erectile dysfunction, lack of sexual desire, inability to orgasm, and lack of intercourse satisfaction were significantly correlated with increasing age of the participants. Methadone dose and duration of methadone treatment were not found to be associated with sexual dysfunction. The level of plasma testosterone significantly declined during methadone treatment, but results from multivariate analysis indicated low levels of testosterone were not the main cause of sexual dysfunction. No correlation between reported depression status and sexual function was found.ConclusionsWhile high levels of sexual dysfunction were reported by heroin-dependent men in our study before and after MMT initiation, MMT appears to be correlated with improved sexual function in the population of the study.

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