Niclosamide ethanolamine attenuates systemic lupus erythematosus and lupus nephritis in MRL/lpr mice

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organ involvement. Lupus nephritis (LN) is a severe manifestation of the disease and the most common cause of mortality in SLE patients. The etiology of LN is multifactorial and accumulating evidence suggests that mitochondrial dysfunction contributes to LN initiation and progression. Mild mitochondrial uncoupler niclosamide ethanolamine salt (NEN) has recently been shown to be efficacious in the treatment of both diabetic kidney disease and non-diabetic adriamycin nephropathy. However, its role in autoimmune kidney disease has not been explored. Here, we report for the first time that NEN attenuated SLE and lupus nephritis in MRL/lpr mice. NEN treatment reduced urinary protein excretion and attenuated glomerular lesions in this model. NEN treatment also decreased urinary excretion of tubular injury biomarkers NGAL and Kim-1, restored renal tubule phenotypic alterations, inhibited tubular proliferation, and suppressed renal interstitial inflammation and fibrosis. In addition, NEN diet supplementation restored redox imbalance, promoted mitochondrial biogenesis, and improved energy dysregulation in the kidney. Importantly, NEN prevented the enlargement of lymph nodes and the spleen, and decreased serum anti-dsDNA antibody levels in the MRL/lpr mice. Therefore, our data suggest that this mild mitochondrial uncoupling agent has great potential for translational application as a novel therapy for autoimmune disease.