From the Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
Department of Cardiology, Division of Internal Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, and.
J Biol Chem. 2019 Jun 21;294(25):9901-9910. doi: 10.1074/jbc.RA119.007904. Epub 2019 May 10.
Healthy kidney structure and environment rely on epithelial integrity and interactions between epithelial cells and other kidney cells. The Ser/Thr kinase 90 kDa ribosomal protein S6 kinase 1 (p90RSK) belongs to a protein family that regulates many cellular processes, including cell motility and survival. p90RSK is predominantly expressed in the kidney, but its possible role in chronic kidney disease (CKD) remains largely unknown. Here, we found that p90RSK expression is dramatically activated in a classic mouse obstructive chronic kidney disease model, largely in the interstitial FSP-1-positive fibroblasts. We generated FSP-1-specific p90RSK transgenic mouse (RSK-Tg) and discovered that these mice, after obstructive injury, display significantly increased fibrosis and enhanced tubular epithelial damage compared with their wt littermates (RSK-wt), indicating a role of p90RSK in fibroblast-epithelial communication. We established an fibroblast-epithelial coculture system with primary kidney fibroblasts from RSK-Tg and RSK-wt mice and found that RSK-Tg fibroblasts consistently produce excessive HO causing epithelial oxidative stress and inducing nuclear translocation of the signaling protein β-catenin. Epithelial accumulation of β-catenin, in turn, promoted epithelial apoptosis by activating the transcription factor forkhead box class O1 (FOXO1). Of note, blockade of reactive oxygen species (ROS) or β-catenin or FOXO1 activity abolished fibroblast p90RSK-mediated epithelial apoptosis. These results make it clear that p90RSK promotes kidney fibrosis by inducing fibroblast-mediated epithelial apoptosis through ROS-mediated activation of β-catenin/FOXO1 signaling pathway.
健康的肾脏结构和环境依赖于上皮完整性以及上皮细胞与肾脏其他细胞之间的相互作用。丝氨酸/苏氨酸激酶 90 kDa 核糖体蛋白 S6 激酶 1（p90RSK）属于一种调节许多细胞过程的蛋白家族，包括细胞运动和存活。p90RSK 主要在肾脏中表达，但它在慢性肾脏病（CKD）中的可能作用在很大程度上仍然未知。在这里，我们发现 p90RSK 表达在经典的小鼠梗阻性慢性肾脏病模型中显著激活，主要在间质 FSP-1 阳性成纤维细胞中。我们生成了 FSP-1 特异性 p90RSK 转基因小鼠（RSK-Tg），并发现这些小鼠在梗阻性损伤后与野生型同窝仔鼠（RSK-wt）相比，纤维化显著增加，肾小管上皮损伤增强，表明 p90RSK 在成纤维细胞-上皮细胞通讯中发挥作用。我们建立了一个原代肾脏成纤维细胞的成纤维细胞-上皮共培养系统，来自 RSK-Tg 和 RSK-wt 小鼠，发现 RSK-Tg 成纤维细胞持续产生过多的 HO 导致上皮氧化应激，并诱导信号蛋白β-catenin 的核转位。上皮细胞β-catenin 的积累，反过来又通过激活转录因子叉头框 O1（FOXO1）促进上皮细胞凋亡。值得注意的是，ROS、β-catenin 或 FOXO1 活性的阻断消除了成纤维细胞 p90RSK 介导的上皮细胞凋亡。这些结果清楚地表明，p90RSK 通过 ROS 介导的β-catenin/FOXO1 信号通路的激活，促进成纤维细胞介导的上皮细胞凋亡，从而促进肾脏纤维化。
