Department of Medicine-Nephrology, West China Hospital of Sichuan University, Chengdu, China.
Lab Invest. 2011 Jun;91(6):837-51. doi: 10.1038/labinvest.2011.42. Epub 2011 Mar 7.
Elevated blood level of C-reactive protein (CRP) is associated with increased risk of chronic kidney disease. However, whether this association reflects functional importance of CRP in the pathogenesis of kidney disease remains unclear. In this study, we examined the biological role of CRP in a well-characterized model of progressive kidney disease, unilateral ureteral obstruction (UUO), in mice that express the human CRP gene (CRPtg). Compared with wild-type (Wt) mice at 3 days after UUO, CRPtg mice developed more severe renal inflammation with a significant increase in tubulointerstitial T cells and macrophages, upregulation of proinflammatory cytokines (IL-1β and TNF-α), chemokines (MCP-1), and adhesion molecules (ICAM-1). Renal fibrosis was also significantly enhanced in CRPtg mice as demonstrated by increased expression of tubulointerstitial α-smooth muscle actin and collagen types I and III compared with Wt mice. Interestingly, on days 7 and 14 after UUO, an equal severity of renal inflammation and fibrosis were observed in CRPtg and Wt mice. These findings suggested that CRP may have a role in the initiation of renal inflammation and fibrosis. Further study revealed that enhanced early renal inflammation and fibrosis on day 3 in CRPtg mice was associated with a significant upregulation of endogenous mouse CRP and FcγRI mRNA and increased activation of both NF-κB/p65 and TGF-β/Smad2/3 signaling, while equal severity of progressive renal injury at day 7 and day 14 between CRPtg and Wt mice were attributed to equivalent levels of CRP, FcγRI, phospho-NF-κB/p65, and TGF-β/Smad2/3 signaling. Based on these findings, we conclude that CRP may not only be a biomarker, but also a mediator in the early development of renal inflammation and fibrosis in a mouse model of UUO. Enhanced activation of both NF-κB and TGF-β/Smad signaling pathways may be mechanisms by which CRP promotes early renal inflammation and fibrosis.
C 反应蛋白（CRP）血液水平升高与慢性肾脏病风险增加有关。然而，这种关联是否反映了 CRP 在肾脏病发病机制中的功能重要性尚不清楚。在这项研究中，我们在一种经过充分表征的进行性肾脏病模型（单侧输尿管梗阻，UUO）中研究了 CRP 在小鼠中的生物学作用，该模型表达了人 CRP 基因（CRPtg）。与 UUO 后 3 天的野生型（Wt）小鼠相比，CRPtg 小鼠发生了更严重的肾脏炎症，肾小管间质 T 细胞和巨噬细胞显著增加，促炎细胞因子（IL-1β 和 TNF-α）、趋化因子（MCP-1）和粘附分子（ICAM-1）表达上调。与 Wt 小鼠相比，CRPtg 小鼠的肾纤维化也显著增强，表现为肾小管间质α-平滑肌肌动蛋白和 I 型和 III 型胶原表达增加。有趣的是，在 UUO 后第 7 天和第 14 天，CRPtg 和 Wt 小鼠的肾脏炎症和纤维化严重程度相同。这些发现表明 CRP 可能在肾脏炎症和纤维化的启动中发挥作用。进一步研究表明，CRPtg 小鼠在第 3 天发生的早期肾脏炎症和纤维化增强与内源性小鼠 CRP 和 FcγRI mRNA 的显著上调以及 NF-κB/p65 和 TGF-β/Smad2/3 信号通路的激活有关，而在第 7 天和第 14 天，CRPtg 和 Wt 小鼠之间的进行性肾损伤严重程度相同归因于 CRP、FcγRI、磷酸化 NF-κB/p65 和 TGF-β/Smad2/3 信号的等效水平。基于这些发现，我们得出结论，CRP 不仅可以作为生物标志物，而且可以作为 UUO 小鼠模型中肾脏炎症和纤维化早期发展的介质。NF-κB 和 TGF-β/Smad 信号通路的增强激活可能是 CRP 促进早期肾脏炎症和纤维化的机制。
