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. 2008 Aug;128(2):259-68.
doi: 10.1016/j.clim.2008.03.508. Epub 2008 May 29.

Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse

John L Svenson  1 , Jackie EuDaly, Phil Ruiz, Kenneth S Korach, Gary S Gilkeson
Affiliations

Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse

John L Svenson et al. Clin Immunol. 2008 Aug.

Abstract

Systemic lupus erythematosus (SLE) occurs nine times more often in females than males. The purpose of this study was to determine the impact of estrogen receptor (ER) null genotypes on disease in lupus prone NZM2410 (NZM) and MRL/lpr mice, as a method to define the role of estrogen receptor signaling in lupus. ER alpha deficient NZM females, but not males, had significantly prolonged survival, reduced proteinuria, renal pathology scores and serum urea nitrogen levels compared to wildtype mice, despite higher serum anti-dsDNA levels. ER alpha deficient MRL/lpr female, but not male, mice also had significantly less proteinuria and renal pathology scores with no effect on autoantibody levels. Deficiency of ER beta had no effect on disease in either strain or sex. Taken together, these data demonstrate a key role for ER alpha, but not ER beta, in the development of lupus like disease, but not autoimmunity, in female NZM and MRL/lpr mice.

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Figures

Figure 1
Figure 1
Proteinuria in ER deficient NZM2410 lupus mice. NZM females with differing ERα genotype were compared for excretion of urine albumin at the various ages indicated. (A) ANOVA analysis demonstrated a significant decrease in proteinuria in ERα deficient females compared to wildtype and heterozygote mice p<0.05 as indicated by the * and φ respectively. (B) The decreased proteinuria in ERα deficient males did not reach statistical significance overall. (C) There was a significant decrease in ERβ deficient females compared to normal mice only at 30 weeks of age. p<0.05 as indicated by the *. (D) No significant differences were noted in males regardless of ERβ genotype. (n=10 in all groups).
Figure 2
Figure 2
Renal pathology in ER deficient NZM2410 lupus mice. Total glomerular pathology scores were determined for female NZM mice of various ERα genotypes. (A) ERα null females had significantly lower pathology score compared to both wildtype and ERα heterozygotes. p<0.05 by Mann–Whitney analysis. (B) Male littermates of various ERα status were also compared for glomerular scores with no significant difference. (C) ERβ null females had a trend towards lower glomerular scores but did not reach statistical significance. Littermate male NZM mice had no difference in pathology regardless of ERβ genotype (D).
Figure 3
Figure 3
Renal immune complex deposition in ERα deficient NZM2410 mice. Female NZM2410 kidneys were analyzed for IgG deposition (A) and C3 deposition (B) in wildtype and ERα deficient mice by immunofluorescence. There was no difference regardless of ERα genotype. Male littermates were similarly examined and compared between wildtype (C) and ERα knockout (D). No statistical difference was observed regardless of ERα. IgG stainings of glomeruli from wildtype and ERα knockout females are shown respectively in (E) and (F).
Figure 4
Figure 4
Survival of ER deficient NZM2410 lupus mice. ERα knockouts and heterozygotes had significantly prolonged survival by Logrank analysis compared to wildtypes (n=10).
Figure 5
Figure 5
Serum anti-dsDNA antibodies in ERα deficient NZM2410 mice. (A) Both wildtype and knockout mice demonstrated an increase in anti-double stranded DNA production that paralleled disease development (n=10). There was a significant increase in anti-dsDNA levels in ERα null females compared to wildtypes (* indicates p<0.05). Similarly, littermate male NZM mice demonstrated an increase in anti-dsDNA production that increased with disease progression (B), but, with no difference between groups (n=10).
Figure 6
Figure 6
Effects of ER deficiency on disease expression in MRL/lpr mice. MRL females with differing ERα genotype were compared for excretion of urine albumin at the various ages indicated (A). Total glomerular pathology scores were determined for female MRL/lpr mice of various ERα genotypes (B). ERα null females had significantly lower pathology score compared to wildtypes. p<0.01 by Mann–Whitney analysis. Female MRL kidneys were analyzed for C3 deposition (C) in wildtype and ERα deficient mice by immunofluorescence. ERα null females had significantly lower deposition compared to wildtype mice. p<0.05 by Mann–Whitney analysis.
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