| First Author | Corradetti C | Year | 2018 |
| Journal | J Immunol | Volume | 200 |
| Issue | 2 | Pages | 512-522 |
| PubMed ID | 29237779 | Mgi Jnum | J:257289 |
| Mgi Id | MGI:6110488 | Doi | 10.4049/jimmunol.1700770 |
| Citation | Corradetti C, et al. (2018) Estrogen Receptor alpha Signaling Exacerbates Immune-Mediated Nephropathies through Alteration of Metabolic Activity. J Immunol 200(2):512-522 |
| abstractText | Glomerulonephritis is one of the most serious manifestations of systemic lupus erythematous (SLE). Because SLE is >/=10 times more common in women, a role for estrogens in disease pathogenesis has long been suspected. Estrogen receptor alpha (ERalpha) is highly expressed in renal tissue. We asked whether ERalpha expression contributes to the development of immune-mediated nephropathies like in lupus nephritis. We tested the overall effects of estrogen receptors on the immune response by immunization with OVA and induction of chronic graft-versus-host disease in female ERalpha-knockout mice. We used nephrotoxic serum nephritis as a model of immune-mediated nephropathy. We investigated the influence of ERalpha on molecular pathways during nephritis by microarray analysis of glomerular extract gene expression. We performed RNA sequencing of lupus patient whole blood to determine common pathways in murine and human nephritis. Absence of ERalpha protects female mice from developing nephritis, despite the presence of immune complexes and the production of proinflammatory cytokines in the kidneys and normal humoral responses to immunization. Time-course microarray analysis of glomeruli during nephrotoxic serum nephritis revealed significant upregulation of genes related to PPAR-mediated lipid metabolism and downregulation of genes in the retinol metabolism in wild-type females compared with ERalpha-knockout females. Similarly, RNA sequencing of lupus patient blood revealed similar expression patterns of these same pathways. During nephritis, the altered activity of metabolic pathways, such as retinol metabolism, occurs downstream of ERalpha activation and is essential for the progression to end-stage renal failure. |
