Activation of annexin A1 signalling in renal fibroblasts exerts antifibrotic effects
Activation of annexin A1 signalling in renal fibroblasts exerts antifibrotic effects
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DOI：
10.1111/apha.12586
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发表时间：
2015-11-01
影响因子：
6.3
通讯作者：
Paliege，A.
中科院分区：
文献类型：
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作者：
Neymeyer，H.;Labes，R.;Paliege，A.
目的抗炎蛋白膜联蛋白A1（AnxA 1）及其甲酰肽受体2（FPR 2）在器官纤维化中具有保护作用。它们在慢性肾病（CKD）中的作用尚未阐明。我们的目的是表征AnxA 1/FPR 2系统在肾纤维化模型中的作用。MethodsRats在肾形成期（ARAn p）用血管紧张素受体拮抗剂处理以诱导迟发性高血压肾病和纤维化。通过定量真实的时间PCR和双标记免疫荧光研究AnxA 1和FPR 2的定位和调节。AnxA 1的生物学效应进行了研究，在培养的肾成纤维细胞从AnxA 1 −/−和野生型mice.ResultsAngiotensin receptor antagonist在肾期肾脏显示基质病灶含有CD 73+成纤维细胞，α-平滑肌肌动蛋白（α-SMA）+肌成纤维细胞和CD 68+巨噬细胞。TGF-β和AnxA 1 mRNA比对照组高约3倍。AnxA 1定位于巨噬细胞和成纤维细胞;肌成纤维细胞呈阴性。FPR 2定位于成纤维细胞、肌成纤维细胞、巨噬细胞和内皮细胞。AnxA 1和FPR 2免疫反应性信号在病灶中增加，成纤维细胞和巨噬细胞表达这两种蛋白质。AnxA 1 −/−成纤维细胞显示α-SMA（7倍）和胶原1A 1（Col 1A 1; 144倍）mRNA水平高于对照组。用TGF-β（22.5 ng mL 24 h−1）处理小鼠WT成纤维细胞可增加α-SMA（9.3倍）和Col 1A 1（4倍）的mRNA水平。这些增加在AnxA 1过表达时大大减弱（分别为1.5倍和1.7倍;P< 0.05）。结论AnxA 1和FPR 2在肾间质中表达丰富，并调节成纤维细胞表型和细胞外基质合成活性。
AimThe anti‐inflammatory protein annexin A1 (AnxA1) and its formyl peptide receptor 2 (FPR2) have protective effects in organ fibrosis. Their role in chronic kidney disease (CKD) has not yet been elucidated. Our aim was to characterize the AnxA1/FPR2 system in models of renal fibrosis.MethodsRats were treated with angiotensin receptor antagonist during the nephrogenic period (ARAnp) to induce late‐onset hypertensive nephropathy and fibrosis. Localization and regulation of AnxA1 and FPR2 were studied by quantitative real‐time PCR and double labelling immunofluorescence. Biological effects of AnxA1 were studied in cultured renal fibroblasts from AnxA1−/−and wild‐type mice.ResultsAngiotensin receptor antagonist during the nephrogenic period kidneys displayed matrix foci containing CD73+fibroblasts, alpha‐smooth muscle actin (a‐SMA)+myofibroblasts and CD68+macrophages. TGF‐βand AnxA1 mRNAs were ~threefold higher than in controls. AnxA1 was localized to macrophages and fibroblasts; myofibroblasts were negative. FPR2 was localized to fibroblasts, myofibroblasts, macrophages and endothelial cells. AnxA1 and FPR2 immunoreactive signals were increased in the foci, with fibroblasts and macrophages expressing both proteins. AnxA1−/−fibroblasts revealed higherα‐SMA (sevenfold) and collagen 1A1 (Col1A1; 144‐fold) mRNA levels than controls. Treatment of murine WT fibroblasts with TGF‐β(22.5 ng mL 24 h−1) increased mRNA levels ofα‐SMA (9.3‐fold) and Col1A1 (fourfold). These increases were greatly attenuated upon overexpression of AnxA1 (1.5‐ and 1.7‐fold, respectively;P< 0.05). Human fibroblasts reacted similarly when receiving the FPR2 inhibitor WRW4.ConclusionOur results demonstrate that AnxA1 and FPR2 are abundantly expressed in the renal interstitium and modulate fibroblast phenotype and extracellular matrix synthesis activity.