Department of Internal Medicine, Chonnam National University Medical School, Gwangju, South Korea.
FASEB J. 2019 Oct;33(10):11109-11122. doi: 10.1096/fj.201900325R. Epub 2019 Jul 12.
Renal fibrosis is the common pathway of chronic kidney disease progression. The nuclear receptor farnesoid X receptor [FXR, NR1H4 (nuclear receptor subfamily 1 group member 4)], a multifunctional transcription factor, plays a pivotal role in protecting against fibrosis. However, the mechanisms underlying these antifibrotic actions of FXR in kidney disease are largely unknown. Here, we show that agonist GW4064-mediated FXR activation inhibits the activity of the nonreceptor tyrosine kinase Src (proto-oncogene tyrosine-protein kinase), which is critical for regulation of yes-associated protein (YAP) phosphorylation and nuclear localization in renal fibrosis. Activation of FXR suppressed renal fibrosis and Tyr416-Src phosphorylation in TGF-β-treated human renal proximal tubule epithelial (HK2) cells. Moreover, GW4064 treatment in HK2 cells increased Ser127 phosphorylation, cytosolic accumulation of YAP, and interaction of the hippo core kinases (Ste20-like kinase 1, large tumor suppressor kinase 1, and salvador homolog 1). Inhibition of Src using PP2 (Src kinase inhibitor) prevented renal fibrosis and increased Ser127 phosphorylation and cytosolic accumulation of YAP. The expression of fibrosis markers, inflammatory genes, and YAP target genes was increased in the kidneys of FXR knockout mice compared with those of wild-type mice. In addition, GW4064 or WAY-362450 (turofexorate isopropyl) treatment protected against unilateral ureteral obstruction-induced renal fibrosis. Collectively, our data support the novel conclusion that Src-mediated crosstalk between FXR and YAP protects against renal fibrosis, making this pathway a possible therapeutic target for chronic kidney disease.-Kim, D.-H., Choi, H.-I., Park, J. S., Kim, C. S., Bae, E. H., Ma, S. K., Kim, S. W. Src-mediated crosstalk between FXR and YAP protects against renal fibrosis.
肾纤维化是慢性肾脏病进展的共同途径。核受体法尼醇 X 受体[FXR，NR1H4（核受体亚家族 1 组成员 4）]，一种多功能转录因子，在防止纤维化方面起着关键作用。然而，FXR 在肾脏疾病中发挥这些抗纤维化作用的机制在很大程度上尚不清楚。在这里，我们表明激动剂 GW4064 介导的 FXR 激活抑制了非受体酪氨酸激酶Src（原癌基因酪氨酸蛋白激酶）的活性，Src 对于调节 yes 相关蛋白（YAP）磷酸化和肾纤维化中的核定位至关重要。FXR 的激活抑制了 TGF-β处理的人肾近端小管上皮（HK2）细胞中的肾纤维化和 Tyr416-Src 磷酸化。此外，GW4064 处理 HK2 细胞增加了 Ser127 磷酸化、YAP 的细胞质积累以及 hippo 核心激酶（Ste20 样激酶 1、大肿瘤抑制激酶 1 和 salvador 同源物 1）的相互作用。使用 PP2（Src 激酶抑制剂）抑制 Src 可防止肾纤维化并增加 Ser127 磷酸化和 YAP 的细胞质积累。与野生型小鼠相比，FXR 敲除小鼠肾脏中纤维化标志物、炎症基因和 YAP 靶基因的表达增加。此外，GW4064 或 WAY-362450（异丙基 turofexorate）治疗可防止单侧输尿管梗阻引起的肾纤维化。总之，我们的数据支持Src 介导的 FXR 和 YAP 之间的串扰可防止肾纤维化的新结论，这使得该途径成为慢性肾脏病的潜在治疗靶点。-Kim，D.-H.，Choi，H.-I.，Park，J. S.，Kim，C. S.，Bae，E. H.，Ma，S. K.，Kim，S. W. Src 介导的 FXR 和 YAP 之间的串扰可防止肾纤维化。
