ER oxidoreductin-1α and unfolded protein response as sex-dependent drivers of cardiorenal dysfunction in experimental autoimmune encephalomyelitis

Background: Multiple sclerosis (MS) is associated with increased cardiovascular and renal morbidity, but mechanisms linking CNS autoimmunity to peripheral organ injury remain poorly defined. We tested the hypothesis that experimental autoimmune encephalomyelitis (EAE) induces cardiorenal dysfunction via sex-specific dysregulation of endoplasmic reticulum (ER) oxidoreductases and unfolded protein response (UPR) signaling. Methods: Adult female and male C57BL/6J mice [10-12 weeks] and IRE1α C148S knock-in mice underwent non-pertussis toxin EAE (nPTX-EAE) induced with 100μg MOG35-55 in CFA and 200μg heat-inactivated MTB with a booster at 7 days. Controls received all components except MOG. Motor scoring was done daily and EN460 (ERO1α inhibitor, 10 mg/kg IP) was given twice weekly beginning at 10DPI. Echocardiography and renal Doppler (Vevo 2100) were performed at 36-38DPI with primary outcomes of LV systolic/diastolic function and renal perfusion with tissue collected at 40DPI. LV and kidney were analyzed via western blot for ERO1α, PDIA1, Prdx4, 4HNE, and BiP. Data are expressed as mean ± SEM with two-way ANOVA/Tukey's post hoc or Mann Whitney test performed and outliers identified by ROUT (Q=1%). Results: Sixty-seven percent of immunized mice developed motor deficits. At 36-38DPI, EAE reduced ejection fraction and fractional shortening while increasing IVCT, IVRT, and myocardial performance index without hypertrophy. Renal resistive index increased and end-diastolic velocity decreased in addition to reduced Bowman's space at 40DPI. Females showed upregulated LV ERO1α and 4HNE while males exhibited reduced PDI and Prdx4 paired with elevated BiP. EN460 attenuated cardiac and renal dysfunction and lowered LV ERO1α/4HNE in females, but not males. IRE1αC148S mitigated cardiac dysfunction in males and restore renal indices in both sexes. Conclusions: nPTX-EAE causes clinically relevant, sex-specific cardiorenal dysfunction linked to distinct ER stress/UPR alterations. ERO1α inhibition protects females, whereas enhanced IRE1α activity protects males and kidneys across sexes, supporting sex-specific ER stress-targeted therapies for MS-associated cardiorenal disease.