Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice
Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice
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DOI：
10.1007/s00125-012-2578-1
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发表时间：
2012-08-01
期刊：
影响因子：
8.2
通讯作者：
Nakao, K.
中科院分区：
文献类型：
--
作者：
Kuwabara, T.;Mori, K.;Nakao, K.
高脂血症是糖尿病肾病发展的独立危险因素，但其分子机制尚不明确。我们在小鼠中研究了糖尿病和高脂血症是如何单独或联合引起肾脏病变的，以及toll样受体4 （TLR4）在这一过程中的作用。通过腹腔注射链脲佐菌素（STZ）诱导野生型（WT）和Tlr4敲除型（KO）小鼠发生糖尿病。注射STZ后2周，用高脂饮食（HFD）代替正常饮食。6周后进行功能和组织学分析。与STZ或HFD单独治疗相比，STZ和HFD联合治疗WT小鼠的肾病明显加重，表现为蛋白尿增加、肾小球系膜扩张、巨噬细胞浸润以及促炎和细胞外基质相关基因表达上调。在Tlr4 KO小鼠中，在STZ中加入HFD对测量的变量几乎没有影响。S100钙结合蛋白A8 （calgranulin A; S100A8）是TLR4的有效配体，在浸润STZ-HFD WT肾小球和糖尿病肾病患者肾小球的巨噬细胞中大量产生。高糖和脂肪酸处理协同上调了WT小鼠巨噬细胞中S100a8基因的表达，但在KO小鼠中没有。作为TLR4的下游靶点，干扰素调节因子3 （IRF3）的磷酸化在STZ和HFD共同治疗的WT小鼠肾脏中增强。在糖尿病肾小球损伤伴高脂血症的动物模型中，S100A8/TLR4信号的激活被阐明，这可能为进行性糖尿病肾病提供新的治疗靶点。
Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process.Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later.Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellular-matrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD.Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.