Leucine rich α-2 glycoprotein is a potential urinary biomarker for renal tubular injury
Leucine rich α-2 glycoprotein is a potential urinary biomarker for renal tubular injury
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DOI：
10.1016/j.bbrc.2018.03.111
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发表时间：
2018-04-15
影响因子：
3.1
通讯作者：
Naka, Tetsuji
中科院分区：
文献类型：
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作者：
Lee, Hyun;Fujimoto, Minoru;Naka, Tetsuji
最近的证据表明，肾小管损伤在慢性肾脏疾病（CKD）和急性肾损伤（AKI）的肾功能恶化中起着关键作用。由于GFR、血清肌酐、血尿素氮、肌酐清除率等常用生化指标不适合检测肾小管的改变，反映肾小管损伤的生物标志物得到了广泛的探索。我们的研究小组发现富含亮氨酸的α -2糖蛋白（LRG）是一种新的血清生物标志物，可用于各种炎症性疾病，如类风湿关节炎和炎症性肠病。在炎症性疾病中，LRG在炎症部位表达上调，这与多种炎症细胞因子诱导LRG在多种细胞类型中的表达一致。最近，尿LRG被报道为几种肾脏疾病的可能生物标志物，但LRG在尿液中的排泄机制尚不清楚。在本研究中，通过分析小鼠白蛋白（ALB）过载模型（通常用于研究蛋白尿诱导的肾小管损伤），我们提供了证据，证明尿LRG是由蛋白尿诱导的肾损伤过程中释放的白细胞介素-1 β (IL-1 β)在肾小管上皮细胞中产生的。在这个模型中，ALB超载后尿LRG可以检测到。在肾脏中，与pbs处理的小鼠相比，alb超载小鼠的LRG、NACHT、LRR和PYD结构域蛋白3 （NLRP3）和IL-1 β的mRNA表达显著上调。病理分析结果显示，alb超载小鼠肾损伤的近端小管、远端小管和集管中均检测到LRG。因此，过量ALB体外刺激小鼠肾皮质小管上皮细胞可导致LRG mRNA表达上调及蛋白分泌，并可被IL-1受体拮抗剂有效阻断。这些结果提示尿LRG可作为一种检测各种肾脏疾病肾小管损伤的生物标志物。(C) 2018爱思唯尔公司版权所有。
Recent evidence suggests that renal tubular injury plays a key role in deterioration of renal function in both chronic kidney disease (CKD) and acute kidney injury (AKI). Since commonly used biochemical indicators such as GFR, serum creatinine, blood urea nitrogen and creatinine clearance are inappropriate for detecting alteration in renal tubules, biomarkers reflecting renal tubular injury have been extensively explored.Our research group identified leucine rich alpha-2 glycoprotein (LRG) as a novel serum biomarker for various inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. In inflammatory diseases, LRG expression is up-regulated at the site of inflammation, in accordance with the induction of LRG in many cell types by various inflammatory cytokines. Recently, urinary LRG was reported as a possible biomarker for several renal diseases, but the mechanism of LRG excretion in urine is still unclear. In this study, by analyzing a mouse albumin (ALB) overload model that is commonly used to study proteinuria-induced renal tubular injury, we provided evidence that urinary LRG is produced in renal tubular epithelial cells by interleukin-1 beta (IL-1 beta) that is released during proteinuria-induced renal damage. In this model, urinary LRG became detectable after ALB overload. In kidney, mRNA expression of LRG together with that of NACHT LRR and PYD domains-containing protein 3 (NLRP3) and IL-1 beta was significantly up-regulated in ALB-overloaded mice, compared to PBS-treated mice. By pathological analysis of kidney, LRG was detected in the injured proximal tubules, distal tubules and collecting ducts in ALB-overloaded mice. Accordingly, in vitro stimulation of mouse renal cortical tubular epithelial cells with excessive ALB led to LRG mRNA up-regulation and its protein secretion, which was effectively blocked by IL-1 receptor antagonist. These results suggest that urinary LRG could be applied to a biomarker detecting renal tubular injury in various renal diseases. (C) 2018 Elsevier Inc. All rights reserved.