PDF(Pubmed)
Abstract：
Lupus nephritis (LN) is a serious complication for many patients who develop systemic lupus erythematosus, which primarily afflicts women. Our studies to identify biomarkers and the pathogenic mechanisms underlying LN will provide a better understanding of disease progression and sex bias, and lead to identification of additional potential therapeutic targets. The glycosphingolipid lactosylceramide (LacCer) and N-linked glycosylated proteins (N-glycans) were measured in urine and serum collected from LN and healthy control (HC) subjects (10 females and 10 males in each group). The sera from the LN and HC subjects were used to stimulate cytokine secretion and intracellular Ca2+ flux in female- and male-derived primary human renal mesangial cells (hRMCs). Significant differences were observed in the urine of LN patients compared to HCs. All major LacCers species were significantly elevated and differences between LN and HC were more pronounced in males. 72 individual N-glycans were altered in LN compared to HC and three N-glycans were significantly different between the sexes. In hRMCs, Ca2+ flux, but not cytokine secretion, was higher in response to LN sera compared to HC sera. Ca2+ flux, cytokine secretion, and glycosphingolipid levels were significantly higher in female-derived compared to male-derived hRMCs. Relative abundance of some LacCers and hexosylceramides were higher in female-derived compared to male-derived hRMCs. Urine LacCers and N-glycome could serve as definitive LN biomarkers and likely reflect renal disease activity. Despite higher sensitivity of female hRMCs, males may experience greater increases in LacCers, which may underscore worse disease in males. Elevated glycosphingolipid metabolism may poise renal cells to be more sensitive to external stimuli.
摘要：
狼疮性肾炎（LN）是许多发展为系统性红斑狼疮的患者的严重并发症，主要折磨女性。我们的研究，以确定生物标志物和潜在的LN的致病机制将提供更好的了解疾病进展和性别偏见，并导致识别其他潜在的治疗靶标。在从LN和健康对照(HC)受试者(每组10名女性和10名男性)收集的尿液和血清中测量鞘糖脂乳糖基神经酰胺(LacCer)和N-连接的糖基化蛋白(N-聚糖)。来自LN和HC受试者的血清用于刺激女性和男性来源的原代人肾系膜细胞（hRMC）中的细胞因子分泌和细胞内Ca2通量。与HC相比，LN患者的尿液中观察到显着差异。所有主要的LacCers物种均显着升高，雄性中LN和HC之间的差异更为明显。与HC相比,LN中的72个个体N-聚糖改变,并且三种N-聚糖在性别之间显著不同。在hRMC中，Ca2+通量，但不是细胞因子分泌，与HC血清相比，对LN血清的反应更高。Ca2+通量，细胞因子分泌，与男性来源的hRMC相比，女性来源的鞘糖脂水平明显更高。与男性来源的hRMC相比，女性来源的某些LacCers和己糖神经酰胺的相对丰度更高。尿液LacCers和N-糖可作为确定的LN生物标志物，并可能反映肾脏疾病的活动性。尽管女性hRMC的敏感性更高，男性可能会经历更多的LacCers增加，这可能突显了男性的更严重疾病。鞘糖脂代谢升高可能使肾细胞对外部刺激更敏感。
