Absence of estrogen receptor alpha in males does not impact disease severity during nephrotoxic serum-induced nephritis

Abstract

Abstract Systemic lupus erythematosus (SLE) exhibits a strong sex bias in which 90% of patients are female. Interestingly, male SLE patients experience greater progression and severity of disease. Glomerulonephritis (GN) remains one of the most serious manifestations of SLE and accounts for most morbidity and mortality among lupus patients. Due to the sex bias, our lab is interested in studying how estrogens may play a role in the pathogenesis of GN and in recent studies we revealed that estrogens exacerbate GN in females in an estrogen receptor alpha- (ERa)-dependent manner by altering activity of metabolic pathways. Although estrogen concentrations are lower, we were interested in investigating whether these sex hormones can also influence disease in males. We found that absence of ERa did not significantly affect the severity of NTS-induced nephritis (NTN) in male mice. Both immune cells and renal cells were involved in NTN progression, and chimera experiments revealed absence of ERa in either of these compartments does not alter the severity of disease. Although absence of ERa in males did not alter NTN disease phenotype, interestingly, analysis of the glomeruli of these mice revealed large differences in gene expression profiles between WT and ERaKO males even if the progression of NTN was similar. WT males exhibited increased expression of genes related to immune activation and cell adhesion, followed by downregulation of metabolic pathways, while ERaKO males undergo very few genetic changes during NTN. From these results, we conclude that ERa does not play a role in GN pathogenesis in males; however, the potential impacts of the gene expression changes induced by its absence warrants further investigation on other aspect of lupus disease.