Abstract
Lupus nephritis represents a common and serious complication of the autoimmune disease Systemic Lupus Erythematosus (SLE). Clinical studies suggest that several proteins related to iron metabolism, including transferrin, serve as urinary biomarkers of lupus nephritis. We previously reported that in female NZBWF1 mice, a commonly used mouse model of SLE with a female sex bias, increased urinary transferrin excretion and renal iron accumulation occur around the onset of albuminuria. The current study investigated whether similar findings occur in male mice of a different mouse model of SLE, the MRL/lpr mouse. Two different cohorts were studied: MRL/lpr mice at an early, pre-albuminuric age (8 weeks), and after developing albuminuria (>100 mg/dL, confirmed by ELISA); age-matched MRL/MpJ control strain mice served for comparison. Urinary transferrin excretion was dramatically increased in the older, albuminuric MRL/lpr mice compared to the age-matched MRL/MpJ (P < 0.05), but there was no significant difference between strains at 8 weeks of age. Similarly, there were no significant differences between strains in renal cortical or outer medullary non-heme iron concentrations at 8 weeks. In the older, albuminuric MRL/lpr mice, renal cortical and outer medullary non-heme iron concentrations were significantly increased compared with age-matched MRL/MpJ mice, as was the expression of the iron storage protein ferritin (P < 0.01). Together, these data show that increased urinary transferrin excretion and renal tissue iron accumulation also occurs in albuminuric male MRL/lpr mice, suggesting that renal iron accumulation may be a feature of multiple mouse models of SLE.
Highlights
The autoimmune disease Systemic Lupus Erythematosus (SLE) affects multiple organ systems in the body, and inflammation and damage to the kidneys is a common and serious complication of SLE
Average kidney weight-to-body weight ratios for 8-week-old Murphy Roth’s (or Recombinant) Large (MRL)/MpJ and MRL/lpr mice were not significantly different between groups (8.0 ± 0.1 vs. 7.7 ± 0.2 mg/g; P = 0.2), nor were they significantly different between older MRL/MpJ and we report evidence of increased urinary transferrin excretion and renal iron accumulation in albuminuric male MRL/lpr mice compared to age-matched MRL/MpJ control mice
The MRL/lpr model significantly affects male as well as female mice, providing a tractable model for the study of SLE manifestations in male mice [15]. These findings build on similar observations previously made in female NZBWF1 mice, which displayed increased renal cortical and outer medullary non-heme iron and increased tubular ferritin expression compared with age-matched female New Zealand White (NZW) control mice [14]
Summary
The autoimmune disease Systemic Lupus Erythematosus (SLE) affects multiple organ systems in the body, and inflammation and damage to the kidneys (lupus nephritis) is a common and serious complication of SLE. While much of the current clinical therapeutic armamentarium for SLE rightly focuses on combating the aberrant immune response and inflammation seen in this autoimmune disease, identification of non-immune mechanisms that contribute to the progression of renal injury in SLE may provide novel complementary therapeutic approaches Consistent with dysregulation of iron homeostasis in SLE, we previously reported increased iron accumulation in the kidneys of female (New Zealand Black × New Zealand White) F1 (NZBWF1) mice compared to age-matched female New Zealand White (NZW) mice near the onset of albuminuria [14] This well-established polygenic model of SLE is created by crossing the New Zealand Black (NZB) mouse, which itself displays an autoimmunemediated hemolytic anemia and an SLE-like syndrome including anti-nuclear auto-antibody production and glomerulonephritis in a small percentage of animals, with the NZW mouse, which greatly increases the prevalence of features of SLE in the F1 offspring, including autoimmunity and development of immune complex-mediated glomerulonephritis [15, 16]. As reviewed recently [20], male SLE patients often have a more aggressive and rapidly progressing clinical course, including a higher incidence of lupus nephritis, highlighting the relevance of studying SLE disease mechanisms in males as well as females
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