Abstract
ObjectiveTo elucidate the role of oxidation resistance 1 (OXR1) gene. Oxidative stress plays a pivotal role in pathogenesis of immune-mediated nephritis. Recently we identified oxidation resistance 1 (OXR1) is conventionally expressed in eukaryotes and has an ability to prevent oxidative damage caused by various oxidative stresses. However the protective effect of OXR1 in immune-associated inflammatory response and oxidative damage is not clear and will be investigated in this study.MethodsWe utilized mesenchymal stem cells (MSCs) as vehicles to carry OXR1 into the injured kidneys of nephritis model mice and investigated the influence of OXR1 on glomerulonephritis. Human OXR1 gene was integrated into genome of MSCs via lentiviral vector, and established hOXR1-MSC cell line which still maintains the differentiation property. 129/svj mice with anti-glomerular basement membrane (GBM) challenge and spontaneous lupus mice B6.Sle1.Sle2.Sle3 were injected with hOXR1-MSCs (i.v. injection) to evaluate the function of hOXR1. Immunohistochemistry was used to appraise the renal pathology and Tunel staining was applied to detect cell apoptosis.ResultsCompared with control mice, hOXR1-MSCs administration showed significantly decreased blood urea nitrogen (BUN), proteinuria and ameliorated renal pathological damage. hOXR1-MSCs transplantation significantly reduced macrophage and T lymphocyte infiltration by inhibiting the expression of CCL2, CCL7, IL-1β, IL-6 and NFκB in mouse kidney. Moreover, hOXR1-MSCs prevented hydrogen peroxide (H2O2)-induced oxidative stress and its implantation reduced nitric oxide (NO) in mouse serum and urine to inhibit tubular cell apoptosis.ConclusionOXR1-MSCs transplantation may exert a certain protective effect on nephritis by suppressing inflammation and oxidative stress.
Highlights
Lupus Nephritis (LN) is a leading cause of morbidity and mortality in Systemic lupus erythematosus (SLE) [1,2], and oxidative stress is a major contributor to disease in LN [3]
Human oxidation resistance 1 (OXR1) gene was integrated into genome of mesenchymal stem cells (MSCs) via lentiviral vector, and established hOXR1-MSC cell line which still maintains the differentiation property. 129/svj mice with anti-glomerular basement membrane (GBM) challenge and spontaneous lupus mice B6.Sle1.Sle2.Sle3 were injected with hOXR1-MSCs (i.v. injection) to evaluate the function of hOXR1
MSCs isolated from mouse bone marrow were characterized by immunocytochemical staining with six markers and were identified morphologically based on their fibroblast-like spindle shape (Figure 1A and 1B), and their differentiation potential to differentiate into osteocytes and adipocytes by culturing the MSCs in appropriate induction media for 3 weeks
Summary
Lupus Nephritis (LN) is a leading cause of morbidity and mortality in Systemic lupus erythematosus (SLE) [1,2], and oxidative stress is a major contributor to disease in LN [3]. Studying the complex interplay of oxidative stress and anti-oxidants may deepen our understanding of the disease, and possibly lead to novel therapeutics. We had previously reported that some strains of mice (such as DBA/1, 129/svj, NZW) are susceptible to anti-GBM nephritis while other mouse strains (such as B6, BALB/c) are not [5,6]. We found that the antioxidant gene, oxidation resistance 1 gene (OXR1) was significantly up-regulated in kidneys of nephritis resistant mice (B6, BALB/c) compared with the sensitive mice (DAB1, 129/svj, NZW) [8]. The increased expression of OXR1 was correlated with the milder inflammation noted in kidney of anti-GBM challenged B6 and BALB/c mice
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