Sublytic C5b-9 triggers glomerular mesangial cell proliferation via enhancing FGF1 and PDGFα gene transcription mediated by GCN5-dependent SOX9 acetylation in rat Thy-1 nephritis
Sublytic C5b-9 triggers glomerular mesangial cell proliferation via enhancing FGF1 and PDGFα gene transcription mediated by GCN5-dependent SOX9 acetylation in rat Thy-1 nephritis
复制标题
Sublytic C5b-9 通过增强大鼠 Thy-1 肾炎中 GCN5 依赖性 SOX9 乙酰化介导的 FGF1 和 PDGFα 基因转录来触发肾小球系膜细胞增殖
DOI：
10.1096/fj.202002814rr
复制
发表时间：
2021-07-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Yingwei
中科院分区：
文献类型：
--
作者：
Liu, Longfei;Ge, Wen;Wang, Yingwei
大鼠Thy-1肾炎（Thy-1N）是人系膜增生性肾小球肾炎（MsPGN）的动物模型，伴有肾小球系膜细胞（GMC）增殖和细胞外基质（ECM）沉积。尽管GMC膜上形成的亚裂解C5b-9可以诱导细胞增殖，但其机制仍不清楚。在这项研究中，我们首先证明，在 Thy-1N 大鼠的肾组织（体内）和 GMC（体外）中，在亚溶解性 C5b-9 刺激下，SRY 相关的 HMG-BOX 基因 9 (SOX9)、一般对照非阻抑基因 5 (GCN5)、成纤维细胞生长因子 1 (FGF1) 和血小板源性生长因子 α (PDGF α) 的水平均升高。随后，我们不仅发现sublytic C5b-9通过增加SOX9、GCN5、FGF1和PDGF α表达来引起GMC增殖，而且证明SOX9和GCN5形成复合物并与FGF1和PDGF α启动子结合，导致FGF1和PDGF α基因转录。更重要的是，GCN5可以介导SOX9在赖氨酸62（K62）处的乙酰化，以增强SOX9与FGF1或PDGFα启动子的结合，并促进FGF1或PDGFα合成和GMC增殖。此外，体内实验还表明，沉默肾脏SOX9、GCN5、FGF1或PDGFα基因后，Thy-1N大鼠的FGF1和PDGFα表达、GMC增殖和尿蛋白分泌大大减少。此外，MsPGN患者的肾组织也表现出上述这些基因的阳性表达。总的来说，我们的研究结果表明 GCN5、SOX9 和 FGF1/PDGF α 可以形成轴，并在亚裂解 C5b-9 触发的 GMC 增殖中发挥重要作用，这可能为 Thy-1N 和 MsPGN 的发病机制提供新的见解。
Rat Thy-1 nephritis (Thy-1N) is an animal model of human mesangioproliferative glomerulonephritis (MsPGN), accompanied by glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) deposition. Although sublytic C5b-9 formed on GMC membrane could induce cell proliferation, the mechanism is still unclear. In this study, we first demonstrated that the level of SRY related HMG-BOX gene 9 (SOX9), general control nonderepressible 5 (GCN5), fibroblast growth factor 1 (FGF1) and platelet-derived growth factor alpha (PDGF alpha) was all elevated both in the renal tissues of Thy-1N rats (in vivo) and in the GMCs (in vitro) with sublytic C5b-9 stimulation. Then, we not only discovered that sublytic C5b-9 caused GMC proliferation through increasing SOX9, GCN5, FGF1 and PDGF alpha expression, but also proved that SOX9 and GCN5 formed a complex and combined with FGF1 and PDGF alpha promoters, leading to FGF1 and PDGF alpha gene transcription. More importantly, GCN5 could mediate SOX9 acetylation at lysine 62 (K62) to enhance SOX9 binding to FGF1 or PDGF alpha promoter and promote FGF1 or PDGF alpha synthesis and GMC proliferation. Besides, the experiments in vivo also showed that FGF1 and PDGF alpha expression, GMC proliferation and urinary protein secretion in Thy-1N rats were greatly reduced by silencing renal SOX9, GCN5, FGF1 or PDGF alpha gene. Furthermore, the renal tissues of MsPGN patients also exhibited positive expression of these genes mentioned above. Collectively, our findings indicate that GCN5, SOX9 and FGF1/PDGF alpha can form an axis and play an essential role in sublytic C5b-9-triggered GMC proliferation, which might provide a novel insight into the pathogenesis of Thy-1N and MsPGN.