Department of Rheumatology, Shenzhen Hospital, Southern Medical University, The Third School of Clinical Medicine, Southern Medical University, China.
Department of Rheumatology, Shenzhen Hospital, Southern Medical University, The Third School of Clinical Medicine, Southern Medical University, China.
Int Immunopharmacol. 2020 Dec;89(Pt A):107027. doi: 10.1016/j.intimp.2020.107027. Epub 2020 Oct 8.
FoxO3a plays key roles in inflammation and autoimmunity, and the PI3K-Akt-FoxO3a pathway has been proposed to modulate diverse biological processes. The aim of the present study, using lupus murine models, was to investigate whether FoxO3a contributes to the pathogenesis of lupus nephritis. LY294002 was used as an inhibitor of PI3K/AKT signaling pathway. FoxO3a-targeted small interfering RNA (siRNA) was also used for in vivo intervention. Female MRL/lpr mice were separately injected with LY294002, LY294002+siFoxO3a, and LY294002+siControl for 8 weeks. C57BL/6 mice were normal controls. Disease development, including serum creatinine (CRE), blood urea nitrogen (BUN), proteinuria, and renal pathological changes, was monitored. Levels of anti-dsDNA antibodies and immune complex (IC) deposition in the kidney were also measured. The expression of proteins was evaluated. We found that significant downregulation of FoxO3a was detected in the kidney of MRL/lpr mice as compared with normal control mice. Blockade of p-FoxO3a activation by LY294002 suppressed PI3K/Akt/FoxO3a pathway and the subsequent upregulation of FoxO3a in the nucleus resulting in the severity of inflammation and fibrosis in the kidney of MRL/lpr mice. Also, improved kidney function and decreased circulating anti-dsDNA antibodies were due to the upregulation of FoxO3a. Opposite results were obtained by specific siRNA silencing of Foxo3a in vivo. In conclusion, our research demonstrated that the upregulation of FoxO3a expression through inhibiting PI3K/Akt pathway attenuates murine lupus nephritis (LN). Thus, our results suggest that targeting of FoxO3a can be considered as a novel strategy for the treatment of LN.
FoxO3a 在炎症和自身免疫中发挥关键作用，并且已经提出 PI3K-Akt-FoxO3a 途径来调节多种生物过程。本研究使用狼疮小鼠模型，旨在研究 FoxO3a 是否有助于狼疮肾炎的发病机制。LY294002 被用作 PI3K/AKT 信号通路的抑制剂。还使用 FoxO3a 靶向的小干扰 RNA（siRNA）进行体内干预。雌性 MRL/lpr 小鼠分别接受 LY294002、LY294002+siFoxO3a 和 LY294002+siControl 注射 8 周。C57BL/6 小鼠作为正常对照。监测疾病发展，包括血清肌酐（CRE）、血尿素氮（BUN）、蛋白尿和肾脏病理变化。还测量了肾脏中抗 dsDNA 抗体和免疫复合物（IC）的沉积水平。评估了蛋白质的表达。我们发现，与正常对照小鼠相比，MRL/lpr 小鼠肾脏中的 FoxO3a 表达明显下调。通过 LY294002 阻断 p-FoxO3a 激活抑制了 PI3K/Akt/FoxO3a 途径，随后 FoxO3a 在核内的上调导致 MRL/lpr 小鼠肾脏的炎症和纤维化加重。此外，由于 FoxO3a 的上调，改善了肾脏功能并减少了循环抗 dsDNA 抗体。通过体内特异性 Foxo3a siRNA 沉默获得了相反的结果。总之，我们的研究表明，通过抑制 PI3K/Akt 途径上调 FoxO3a 表达可减轻小鼠狼疮肾炎（LN）。因此，我们的结果表明，针对 FoxO3a 可以被认为是治疗 LN 的一种新策略。
