Abstract
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 α (ERα) is highly expressed in renal tissue. We asked whether ERα 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 ERα-knockout mice. We used nephrotoxic serum nephritis as a model of immune-mediated nephropathy. We investigated the influence of ERα 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 ERα 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 ERα-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 ERα activation and is essential for the progression to end-stage renal failure.
Footnotes
This work was supported by National Institutes of Health–National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01-AR061569-01A1 (to R.C.).
Microarray data presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE98626) under accession number GSE98626.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- B6
- C57BL/6
- BUN
- blood urea nitrogen
- cGVHD
- chronic graft-versus-host disease
- EGF
- epidermal growth factor
- ERα
- estrogen receptor α
- KO
- knockout
- LN
- lupus nephritis
- Ltf
- lactotransferrin
- NTN
- NTS-induced nephritis
- NTS
- nephrotoxic serum
- Pgr
- progesterone receptor
- SLE
- systemic lupus erythematosus
- SMA
- smooth muscle actin
- TAC
- Transcriptome Analysis Console
- WT
- wild-type.
- Received May 26, 2017.
- Accepted October 31, 2017.
- Copyright © 2018 by The American Association of Immunologists, Inc.
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