Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts
Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts
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DOI：
10.1681/asn.2017010110
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发表时间：
2017-11-01
影响因子：
13.6
通讯作者：
Cantley, Lloyd G.
中科院分区：
文献类型：
--
作者：
Montgomery, Tinika A.;Xu, Leyuan;Cantley, Lloyd G.
对肾损伤的正常反应包括中性粒细胞和巨噬细胞的强烈炎性浸润。我们先前表明，小分泌蛋白乳腺退化蛋白-39（BRP-39），也称为几丁质酶3样1（CHI 3L 1），由Chi 3 I1基因编码，在肾修复的早期阶段由巨噬细胞高水平表达，并通过IL-13受体α 2（IL 13 R α 2）介导的信号传导促进肾小管细胞存活。在这里，我们研究了BRP-39在阿基后促纤维化反应中的作用。在野生型小鼠中，单侧缺血再灌注损伤（U-IRI）后未能解决肾小管损伤导致肾细胞持续低水平Chi 3 I1 mRNA表达，并促进巨噬细胞持续存在和严重的间质纤维化。对U-IRI后14天从野生型肾分离的巨噬细胞的分析显示促纤维化BRP-39受体Ptgdr 2/Crth 2的高水平表达和促纤维化标志物Lgals 3、Pdgfb、Egf和Tgfb的表达。相比之下，来自缺乏BRP-39的小鼠的受损肾脏具有显著更少的巨噬细胞，促纤维化生长因子的表达减少，并且细胞外基质的积累减少。BRP-39耗竭不影响肌成纤维细胞蓄积，但减弱了Collet Col 3a 1和Fn 1的肌成纤维细胞表达。总之，这些结果将BRP-39鉴定为巨噬细胞-肌成纤维细胞串扰和促纤维化信号传导在适应不良的肾修复环境中的重要激活剂。
The normal response to kidney injury includes a robust inflammatory infiltrate of PMNs and macrophages. We previously showed that the small secreted protein breast regression protein-39 (BRP-39), also known as chitinase 3-like 1 (CHI3L1) and encoded by the Chi3I1 gene, is expressed at high levels by macrophages during the early stages of kidney repair and promotes tubular cell survival via IL-13 receptor alpha 2 (IL13R alpha 2)mediated signaling. Here, we investigated the role of BRP-39 in profibrotic responses after AKI. In wild type mice, failure to resolve tubular injury after unilateral ischemia-reperfusion injury (U-IRI) led to sustained low-level Chi3I1 mRNA expression by renal cells and promoted macrophage persistence and severe interstitial fibrosis. Analysis of macrophages isolated from wild-type kidneys 14 days after U-IRI revealed high-level expression of the profibrotic BRP-39 receptor Ptgdr2/Crth2 and expression of the profibrotic markers Lgals3, Pdgfb, Egf, and Tgfb. In comparison, injured kidneys from mice lacking BRP-39 had significantly fewer macrophages, reduced expression of profibrotic growth factors, and decreased accumulation of extracellular matrix. BRP-39 depletion did not affect myofibroblast accumulation but did attenuate myofibroblast expression of Collet Col3a1, and Fn1. Together, these results identify BRP-39 as an important activator of macrophage-myofibroblast crosstalk and profibrotic signaling in the setting of maladaptive kidney repair.