Resident fibroblasts in the kidney: a major driver of fibrosis and inflammation.
Resident fibroblasts in the kidney: a major driver of fibrosis and inflammation.
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DOI：
10.1186/s41232-017-0048-3
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发表时间：
2017
影响因子：
8.1
通讯作者：
Yanagita M
中科院分区：
文献类型：
--
作者：
Sato Y;Yanagita M
慢性肾脏病（CKD）是全球终末期肾脏病（ESRD）和心血管疾病发病率和死亡率的主要原因，导致日益严重的社会和经济负担。由于老龄化，预计CKD的患病率和负担在未来几十年将进一步增加。在CKD的发病机制中，无论病因如何，常驻成纤维细胞都是关键参与者，并已被证明在疾病的发生和进展中发挥关键作用。作为对损伤的响应，驻留的成纤维细胞转分化为表达α平滑肌肌动蛋白（αSMA）的肌成纤维细胞，并具有产生大量细胞外基质（ECM）蛋白的能力增加，导致肾纤维化。除了成纤维细胞作为肾纤维化驱动因素的基本作用外，越来越多的证据表明，常驻成纤维细胞也积极参与肾损伤期间的炎症启动和促进。在上述肌成纤维细胞转化过程中，驻留的成纤维细胞激活NF-κB信号传导并产生促炎细胞因子和趋化因子，从而促进炎症。此外，在老化环境下，响应于损伤和协调三级淋巴组织（TLT）形成，常驻成纤维细胞转分化成几种不同的表型成纤维细胞，包括产生CXCL 13/CCL 19的成纤维细胞、产生视黄酸的成纤维细胞和滤泡树突状细胞，这导致不受控制的异常炎症并延缓组织修复。抗炎剂可以改善肌成纤维细胞转分化并消除TLT形成，这表明靶向这些炎性成纤维细胞可以潜在地改善肾脏疾病。除了其作为纤维化执行者的传统作用外，常驻成纤维细胞显示出更多的促炎表型，并在肾损伤期间积极促进炎症。
Chronic kidney disease (CKD) is a leading cause of end stage renal disease (ESRD) and cardiovascular morbidity and mortality worldwide, resulting in a growing social and economic burden. The prevalence and burden of CKD is anticipated to further increase over the next decades as a result of aging. In the pathogenesis of CKD, irrespective of the etiology, resident fibroblasts are key players and have been demonstrated to play crucial roles for disease initiation and progression. In response to injury, resident fibroblasts transdifferentiate into myofibroblasts that express alpha smooth muscle actin (αSMA) and have an increased capacity to produce large amounts of extracellular matrix (ECM) proteins, leading to renal fibrosis. In addition to this fundamental role of fibroblasts as drivers for renal fibrosis, growing amounts of evidence have shown that resident fibroblasts are also actively involved in initiating and promoting inflammation during kidney injury. During the myofibroblastic transition described above, resident fibroblasts activate NF-κB signaling and produce pro-inflammatory cytokines and chemokines, promoting inflammation. Furthermore, under aging milieu, resident fibroblasts transdifferentiate into several distinct phenotypic fibroblasts, including CXCL13/CCL19-producing fibroblasts, retinoic acid-producing fibroblasts, and follicular dendritic cells, in response to injury and orchestrate tertiary lymphoid tissue (TLT) formation, which results in uncontrolled aberrant inflammation and retards tissue repair. Anti-inflammatory agents can improve myofibroblastic transdifferentiation and abolish TLT formation, suggesting that targeting these inflammatory fibroblasts can potentially ameliorate kidney disease. Beyond its conventional role as an executor of fibrosis, resident fibroblasts display more pro-inflammatory phenotypes and contribute actively to driving inflammation during kidney injury.