Division of Nephrology and Hypertension, Department of Medicine, Nashville, TN, USA.
Vanderbilt Center for Kidney Disease, Nashville, TN, USA.
Nat Commun. 2023 Nov 14;14(1):7357. doi: 10.1038/s41467-023-43226-x.
Fibrosis is the progressive accumulation of excess extracellular matrix and can cause organ failure. Fibrosis can affect nearly every organ including kidney and there is no specific treatment currently. Although Epidermal Growth Factor Receptor (EGFR) signaling pathway has been implicated in development of kidney fibrosis, underlying mechanisms by which EGFR itself mediates kidney fibrosis have not been elucidated. We find that EGFR expression increases in interstitial myofibroblasts in human and mouse fibrotic kidneys. Selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins. In vivo and in vitro studies and single-nucleus RNA sequencing analysis demonstrate that EGFR activation does not induce myofibroblast transformation but is necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by TGF-ß or other profibrotic factors. These findings may also provide insight into development of fibrosis in other organs and in other conditions.
纤维化是细胞外基质的过度积累，可导致器官衰竭。纤维化几乎可以影响所有器官，包括肾脏，目前尚无特定的治疗方法。尽管表皮生长因子受体 (EGFR) 信号通路已被牵涉到肾脏纤维化的发展中，但 EGFR 本身介导肾脏纤维化的潜在机制尚未阐明。我们发现 EGFR 表达在人类和小鼠纤维化肾脏的间质肌成纤维细胞中增加。在单侧输尿管梗阻、缺血或肾毒素反应中，选择性地在成纤维细胞/周细胞群体中缺失 EGFR 可抑制间质纤维化。体内和体外研究以及单核 RNA 测序分析表明，EGFR 激活不会诱导肌成纤维细胞转化，但对于 TGF-β或其他促纤维化因子引起的后续肌成纤维细胞转化之前，EGFR 激活对于初始周细胞/成纤维细胞迁移和增殖是必需的。这些发现还可能为其他器官和其他情况下的纤维化发展提供一些思路。
