ER oxidoreductin-1 α and unfolded protein response as sex-dependent drivers of cardiorenal dysfunction in experimental autoimmune encephalomyelitis
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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 IRE1 α C148S knock-in mice underwent non-pertussis toxin EAE (nPTX-EAE) induced with 100µg MOG 35-55 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 (ERO1 α 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 ERO1 α , 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 ERO1 α and 4HNE while males exhibited reduced PDI and Prdx4 paired with elevated BiP. EN460 attenuated cardiac and renal dysfunction and lowered LV ERO1 α /4HNE in females, but not males. IRE1 α C148S 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. ERO1 α inhibition protects females, whereas enhanced IRE1 α activity protects males and kidneys across sexes, supporting sex-specific ER stress–targeted therapies for MS-associated cardiorenal disease.
