Inhibitor of differentiation 3, a transcription factor, regulates hyperlipidemia-associated kidney disease.
Inhibitor of differentiation 3, a transcription factor, regulates hyperlipidemia-associated kidney disease.
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分化抑制剂 3 是一种转录因子，可调节与高脂血症相关的肾脏疾病。
DOI：
10.1159/000362452
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
Bagavant,Harini
中科院分区：
文献类型：
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作者：
Nackiewicz,Dominika;Dey,Paromita;Szczerba,Barbara;Mohammad,Saleh;Kaplan,JenniferL;McNamara,ColeenA;Deshmukh,UmeshS;Bagavant,Harini
背景脂蛋白异常与慢性肾脏疾病患者肾功能的快速下降有关。此外，高脂血症与发展为肾功能不全的风险增加有关。这些临床发现的潜在分子机制尚不清楚。我们之前已经报道了分化抑制因子3(ID3)在调节高脂血症肾脏疾病中的作用。在自发性高脂血症载脂蛋白E基因敲除(APOE-/-)小鼠中引入ID3基因缺陷导致加速的系膜增生性肾小球肾炎。本研究旨在进一步探讨ID3在高脂血症肾病中的作用。方法雌性野生型(WT)和ID3缺陷型(ID3-/-)C57BL/6小鼠以西式饲料喂养，观察其蛋白尿、肾小球病理和免疫浸润细胞的变化。原代培养的系膜细胞系来源于两个品系的小鼠，并用氧化磷脂刺激。细胞因子和趋化因子的产生通过多重分析、酶联免疫吸附试验和定量聚合酶链式反应进行检测。结果与WT对照组相比，给予西餐的Id3-/-小鼠出现了加速蛋白尿和系膜增生性肾炎。在体外，ID3-/-肾小球系膜细胞系产生更高水平的单核细胞趋化因子CXCL1，以响应氧化磷脂。这与喂养西方饮食的ID3-/-小鼠肾小球CXCL1表达迅速增加，随后巨噬细胞浸润一致。结论功能性ID3通过调节局部趋化因子的产生和炎性细胞的募集，影响肾脏疾病的易感性，防止肾小球损伤。
BackgroundLipoprotein abnormalities are associated with a rapid decline in renal function in patients of chronic kidney disease. In addition, hyperlipidemia is associated with an increased risk of developing renal insufficiency. The underlying molecular mechanisms for these clinical findings are unclear. We have previously reported a role for inhibitor of differentiation 3 (ID3), a transcription factor, in regulating kidney disease in hyperlipidemia. Introducing a genetic deficiency of Id3 in spontaneously hyperlipidemic apolipoprotein E knockout (Apoe-/-) mice led to accelerated mesangioproliferative glomerulonephritis. The present study was carried out to further investigate the contribution of ID3 in hyperlipidemia-associated kidney disease.MethodsFemale C57BL/6 mice that were ID3-sufficient wild-type (WT) or ID3-deficient (Id3-/-) were fed a Western diet and evaluated for proteinuria, glomerular pathology, and immune infiltrating cells. Primary mesangial cell lines were generated from both mouse strains and stimulated with oxidized phospholipids. Cytokines and chemokines produced were measured by multiplex assays, ELISA, and QPCR. Glomerular isolates were studied for CXCL1 expression by QPCR.ResultsId3-/-mice on a Western diet developed accelerated proteinuria and mesangioproliferative glomerulonephritis compared to WT controls. In vitro, Id3-/-glomerular mesangial cell lines produced higher levels of the monocyte chemoattractant CXCL1 in response to oxidized phospholipids. This was consistent with the rapid increase in glomerular CXCL1 expression followed by macrophage infiltration in Id3-/-mice fed a Western diet.ConclusionsA functional ID3 influences susceptibility to kidney disease and prevents glomerular injury by regulating local chemokine production and inflammatory cell recruitment.