Background/Purpose:

Glomerulonephritis (GN) is one of the most serious manifestations of systemic lupus erythematous (SLE). Lupus GN is characterized by severe inflammation and necrosis and it accounts for most morbidity and mortality. Although SLE occurs more often in women, both sexes develop GN and in males often develops earlier and is more severe. There is sex bias in SLE and estrogens may play an important role in GN susceptibility and progression. Interestingly, estrogen receptor alpha (ER-α) in the renal tissue is highly expressed and the renal specific estrogen-induced gene activation is second only to that of reproductive organs. Therefore, we investigated the impact of estrogens on the development of nephritis in both males and female mice by using an inducible model of immune-mediated nephropathy.

Methods: We first investigated the functional status of the immune system in the ER-α KO mice by immunizing them with standard foreign antigen (OVA). We then used the nephrotoxic serum induced nephritis (NTN) model to induce GN in the ER-α KO mice. ER-α WT littermates were used as control. Progression of renal disease was monitored by blood urea nitrogen and body weight. Renal damage was also assessed by histology. Nephrotoxic serum binding and immune complex deposition were determined by immunofluorescence. Quantitative real-time PCR was also performed to measure expression of TNF-α, IL-6, and MCP-1 in the kidneys of KO and WT mice. 

Results:

We found that the ER-α KO and WT mice produced similar levels of anti-OVA antibodies upon OVA antigen immunization (p=n.s.). These results suggest that the lack of ER-α does not grossly impair the immune response.  We also found that the lack of ER-α protects from NTN as the KO mice have significantly less kidney disease than the WT (p<0.05). The most striking differences were less glomerular cellular proliferation and fibrosis. Both sexes were protected albeit the males to a lesser extent. Importantly the NTN model was fully functional in the ER-α KO, as both strains of mice had similar levels of immune complex deposition within the glomeruli; both ER-α KO and WT mice increased the expression of pro-inflammatory cytokines such as TNF-α and IL-6 suggesting that the immune and inflammatory response were similar but that the differences in cellular damage were responsible for the renal protection.

Conclusion: Our results demonstrate that the lack of ER-α allows appropriate immune response but nevertheless protects from NTN, a model of lupus GN. Moreover, our results demonstrate that the protection is secondary to a reduced cellular damage rather than an impairment of the immune system. Interestingly, estrogens influenced the renal outcome also in males albeit to a lesser degree. Based on these results we conclude that estrogens not only play a role in predisposing to SLE but also are important in regulating the cell damage during GN.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/absence-of-estrogen-receptor-alpha-is-protective-against-nephrotoxic-serum-induced-nephritis/