Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
J Am Soc Nephrol. 2013 Sep;24(9):1399-412. doi: 10.1681/ASN.2012050512. Epub 2013 Jun 13.
Injury to the adult kidney induces a number of developmental genes thought to regulate repair, including Wnt4. During kidney development, early nephron precursors and medullary stroma both express Wnt4, where it regulates epithelialization and controls smooth muscle fate, respectively. Expression patterns and roles for Wnt4 in the adult kidney, however, remain unclear. In this study, we used reporters, lineage analysis, and conditional knockout or activation of the Wnt/β-catenin pathway to investigate Wnt4 in the adult kidney. Proliferating, medullary, interstitial myofibroblasts strongly expressed Wnt4 during renal fibrosis, whereas tubule epithelia, except for the collecting duct, did not. Exogenous Wnt4 drove myofibroblast differentiation of a pericyte-like cell line, suggesting that Wnt4 might regulate pericyte-to-myofibroblast transition through autocrine signaling. However, conditional deletion of Wnt4 in interstitial cells did not reduce myofibroblast proliferation, cell number, or myofibroblast gene expression during fibrosis. Because the injured kidney expresses multiple Wnt ligands that might compensate for the absence of Wnt4, we generated a mouse model with constitutive activation of canonical Wnt/β-catenin signaling in interstitial pericytes and fibroblasts. Kidneys from these mice exhibited spontaneous myofibroblast differentiation in the absence of injury. Taken together, Wnt4 expression in renal fibrosis defines a population of proliferating medullary myofibroblasts. Although Wnt4 may be dispensable for myofibroblast transformation, canonical Wnt signaling through β-catenin stabilization is sufficient to drive spontaneous myofibroblast differentiation in interstitial pericytes and fibroblasts, emphasizing the importance of this pathway in renal fibrosis.
成人肾脏损伤会诱导许多被认为可调节修复的发育基因，包括 Wnt4。在肾脏发育过程中，早期肾单位前体细胞和髓质基质均表达 Wnt4，分别调节上皮化和控制平滑肌命运。然而，Wnt4 在成人肾脏中的表达模式和作用仍不清楚。在这项研究中，我们使用报告基因、谱系分析以及 Wnt/β-catenin 通路的条件敲除或激活来研究成年肾脏中的 Wnt4。在肾脏纤维化过程中，增殖的、髓质的、间质成肌纤维细胞强烈表达 Wnt4，而除集合管外的肾小管上皮细胞则不表达。外源性 Wnt4 驱动周细胞样细胞系的成肌纤维细胞分化，表明 Wnt4 可能通过自分泌信号调节周细胞向成肌纤维细胞的转化。然而，间质细胞中 Wnt4 的条件缺失并没有减少纤维化过程中成肌纤维细胞的增殖、细胞数量或成肌纤维细胞基因表达。由于受损的肾脏表达多种可能补偿 Wnt4 缺失的 Wnt 配体，我们生成了一种在间质周细胞和成纤维细胞中组成性激活经典 Wnt/β-catenin 信号的小鼠模型。这些小鼠的肾脏在没有损伤的情况下自发出现成肌纤维细胞分化。总之，Wnt4 在肾脏纤维化中的表达定义了一群增殖的髓质成肌纤维细胞。尽管 Wnt4 对于成肌纤维细胞转化可能不是必需的，但通过β-catenin 稳定的经典 Wnt 信号足以驱动间质周细胞和成纤维细胞中自发的成肌纤维细胞分化，强调了该途径在肾脏纤维化中的重要性。
