Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Sci Rep. 2017 Jun 9;7(1):3192. doi: 10.1038/s41598-017-02915-6.
The mechanisms triggering renal inflammation in chronic kidney disease (CKD) are unclear. We performed a detailed analysis of the time course of innate and adaptive immunity activation in the 5/6 renal ablation (Nx) model. Munich-Wistar rats undergoing Nx were studied 15, 60 and 120 days after ablation. Hypertension, albuminuria, creatinine retention, interstitial expansion and infiltration by macrophages and T-lymphocytes were already evident 15 days after Nx. PCR-array was used to screen for altered gene expression, whereas gene and protein expressions of TLR4, CASP1, IL-1β and NLRP3 were individually assessed. Tlr4, Tlr5, Lbp, Nlrp3, Casp1, Irf7 and Il1b were already upregulated 15 days after Nx, while activation of Tlr2, Tlr7, Tlr9, Nod2, Tnf and Il6 was seen after 60 days post-ablation. The number of genes related to innate or adaptive immunity grew steadily with time. These observations indicate that parallel activation of innate and adaptive immunity antecedes glomerular injury and involves a growing number of intricate signaling pathways, helping to explain the difficulty in detaining renal injury in Nx as CKD advances, and, stressing the need for early treatment. Additionally, these findings may contribute to the search of therapeutic targets specific for advanced phases of CKD.
慢性肾脏病 (CKD) 中触发肾脏炎症的机制尚不清楚。我们对 5/6 肾切除术 (Nx) 模型中固有和适应性免疫激活的时程进行了详细分析。在 Nx 后 15、60 和 120 天，研究了接受 Nx 的慕尼黑-维斯塔大鼠。在 Nx 后 15 天，就已经出现了高血压、白蛋白尿、肌酐潴留、间质扩张以及巨噬细胞和 T 淋巴细胞浸润。PCR 芯片用于筛选改变的基因表达，而 TLR4、CASP1、IL-1β 和 NLRP3 的基因和蛋白表达则分别进行评估。在 Nx 后 15 天，Tlr4、Tlr5、Lbp、Nlrp3、Casp1、Irf7 和 Il1b 已经上调，而 Tlr2、Tlr7、Tlr9、Nod2、Tnf 和 Il6 的激活则在 Nx 后 60 天出现。与固有或适应性免疫相关的基因数量随着时间的推移而稳步增加。这些观察结果表明，固有和适应性免疫的平行激活先于肾小球损伤，并涉及越来越多的复杂信号通路，有助于解释为什么在 CKD 进展过程中难以阻止肾脏损伤，并且强调了早期治疗的必要性。此外，这些发现可能有助于寻找针对 CKD 晚期的治疗靶点。
