C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes
C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes
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DOI：
10.1007/s00125-011-2237-y
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发表时间：
2011-10-01
期刊：
影响因子：
8.2
通讯作者：
Lan, H. Y.
中科院分区：
文献类型：
--
作者：
Liu, F.;Chen, H. Y.;Lan, H. Y.
尽管c反应蛋白（CRP）已被认为是糖尿病的危险因素，但其在糖尿病肾病（DKD）中的致病重要性尚不清楚。本研究探讨了CRP在DKD中的潜在作用。用链脲佐菌素诱导人CRP转基因小鼠和野生型小鼠24周时的肾损伤，采用实时荧光定量PCR、免疫组织化学和western blot分析。在体外，用高糖和/或CRP培养的人肾小管上皮细胞研究CRP的致病作用。我们发现，与野生型小鼠相比，CRP转基因小鼠出现了更严重的糖尿病肾损伤，尿白蛋白排泄和肾损伤分子-1丰度显著增加，巨噬细胞和T细胞浸润增强，促炎细胞因子（IL-1 β, TNF α）和细胞外基质（胶原I， III和IV）上调。在CRP转基因小鼠中，肾脏炎症和纤维化的增强与CRP受体CD32a的上调以及tgf - β /SMAD和核因子κ B信号通路的过度激活有关。在体外，CRP通过CD32a/64显著上调促炎因子（IL-1 β、TNF α、单核细胞趋化蛋白-1 [MCP-1]）和促纤维化生长因子（tgf - β 1、结缔组织生长因子[CTGF]）。高糖诱导CRP，协同促进高糖介导的肾脏炎症和纤维化。CRP不仅是一种生物标志物，也是DKD的中介。tgf - β /SMAD和核因子κ B信号通路的增强激活可能是CRP促进糖尿病患者肾脏炎症和纤维化的机制。
Although C-reactive protein (CRP) has been implicated as a risk factor in diabetes, its pathogenic importance in diabetic kidney disease (DKD) remains unclear. The present study investigated the potential role of CRP in DKD.Diabetes was induced by streptozotocin in human CRP transgenic and wild-type mice for assessment of kidney injury at 24 weeks by real-time PCR, immunohistochemistry and western blot analysis. In vitro, the pathogenic effect of CRP was investigated using human kidney tubular epithelial cells cultured with high glucose and/or CRP.We found that CRP transgenic mice developed much more severe diabetic kidney injury than wild-type mice, as indicated by a significant increase in urinary albumin excretion and kidney injury molecule-1 abundance, enhanced infiltration of macrophages and T cells, and upregulation of pro-inflammatory cytokines (IL-1 beta, TNF alpha) and extracellular matrix (collagen I, III and IV). Enhanced renal inflammation and fibrosis in CRP transgenic mice was associated with upregulation of CRP receptor, CD32a, and over-activation of the TGF-beta/SMAD and nuclear factor kappa B signalling pathways. In vitro, CRP significantly upregulated pro-inflammatory cytokines (IL-1 beta, TNF alpha, monocyte chemoattractant protein-1 [MCP-1]) and pro-fibrotic growth factors (TGF-beta 1, connective tissue growth factor [CTGF]) via CD32a/64. CRP was induced by high glucose, which synergistically promoted high glucose-mediated renal inflammation and fibrosis.CRP is not only a biomarker, but also a mediator in DKD. Enhanced activation of TGF-beta/SMAD and nuclear factor kappa B signalling pathways may be the mechanisms by which CRP promotes renal inflammation and fibrosis under diabetic conditions.