Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
Department of Orthopedics, The Affiliated Hospital of Qingdao University, 59 Hai Er Road, Qingdao, Shandong, 266061, P.R. China.
J Orthop Surg Res. 2021 May 5;16(1):297. doi: 10.1186/s13018-021-02451-0.
Angiotensin II (Ang II) is associated with rheumatoid arthritis (RA) development. The present study investigated the impact of Ang II on the expression of receptor activator of nuclear factor-κB ligand (RANKL), as well as of nuclear factor of activated T cells cytoplasmic 1 (NFATC1) in RA synovial cells, and explored the underlying mechanism.
The expression levels of RANKL, NFATC1, and Ang II type 1 receptor (AT1R) were analyzed by RT PCR, western-blot, and/or immunohistochemistry. Western blot was also used to analyze the p38MAPK, JNK, and ERK1/2 pathways.
The expressions of RANKL and NFATC1 increased in synovial tissues of RA compared to osteoarthritis (OA) synovial tissues. The expression of RANKL was upregulated by Ang II, and this effect was mitigated by an AT1R blocker but not by an AT2R blocker. Furthermore, Ang II activated the ERK1/2, JNK, and p38MAPK pathways, and this effect was blocked by the AT1R blocker. However, ERK1/2 and JNK inhibitors, but not a p38MAPK inhibitor, blocked Ang II-induced RANKL expression. Ang II also increased the level of NFATC1, and this upregulation was attenuated by AT1R blockade, ERK1/2 and JNK inhibition, and siRNA-mediated RANKL silencing, but not by AT2R blockade or p38MAPK inhibition.
Our results indicated that Ang II activated the ERK1/2 and JNK pathways via AT1R, thus upregulating RANKL and NFATC1 expressions in RA synovial cells.
血管紧张素 II（Ang II）与类风湿关节炎（RA）的发展有关。本研究探讨了 Ang II 对 RA 滑膜细胞中核因子活化 T 细胞胞浆 1（NFATC1）和核因子κB 受体激活剂配体（RANKL）表达的影响，并探讨了其潜在机制。
采用 RT-PCR、western blot 和/或免疫组化分析 RANKL、NFATC1 和血管紧张素 II 型 1 受体（AT1R）的表达水平。Western blot 还用于分析 p38MAPK、JNK 和 ERK1/2 通路。
与骨关节炎（OA）滑膜组织相比，RA 滑膜组织中 RANKL 和 NFATC1 的表达增加。Ang II 上调了 RANKL 的表达，这种作用可被 AT1R 阻滞剂减轻，但不能被 AT2R 阻滞剂减轻。此外，Ang II 激活了 ERK1/2、JNK 和 p38MAPK 通路，这种作用可被 AT1R 阻滞剂阻断。然而，ERK1/2 和 JNK 抑制剂，但不是 p38MAPK 抑制剂，阻断了 Ang II 诱导的 RANKL 表达。Ang II 还增加了 NFATC1 的水平，这种上调可被 AT1R 阻断、ERK1/2 和 JNK 抑制以及 RANKL siRNA 沉默减轻，但不能被 AT2R 阻断或 p38MAPK 抑制减轻。
我们的结果表明，Ang II 通过 AT1R 激活 ERK1/2 和 JNK 通路，从而上调 RA 滑膜细胞中 RANKL 和 NFATC1 的表达。
