安徽医科大学汪庆童等共同合作，近期取得重要工作进展。他们研究提出，G蛋白偶联受体激酶2（GRK2）可以作为斯约格伦综合征腺体纤维化的新治疗靶点。相关研究成果2024年7月25日在线发表于《中国药理学报》杂志上。

据介绍，斯约格伦综合征（SS）是一种以腺体纤维化为特征的慢性进行性自身免疫性疾病。研究人员发现腺体纤维化与G蛋白偶联受体激酶2（GRK2）的表达密切相关。

研究人员探讨了GRK2在SS中的病理和治疗意义。通过在WT和GRK2^+/-小鼠中建立了颌下腺（SMG）抗原诱导的SS小鼠模型，研究人员发现，在SS患者和小鼠的腺体组织中，GRK2的表达水平显著上调，并与纤维化形态呈正相关。半合子敲除GRK2显著抑制了腺体纤维化。在小鼠唾液腺上皮细胞（SGEC）中，研究人员证明GRK2与Smad2/3相互作用，通过TGF-β-GRK2正反馈环积极调节TGF-β-Smad信号的激活，从而导致腺体纤维化。

GRK2的半合敲除在体外减弱了TGF-β诱导的SGEC中I型胶原的产生，并通过阻止Smad2/3核易位阻碍了小鼠SS的腺体纤维化。用SMG抗原免疫后约28天，用特异性GRK2抑制剂帕罗西汀（Par，5 mg·kg^-1·d^-1，i.g，持续19天）治疗WT SS小鼠。研究人员发现，Par给药显著减轻了小鼠的腺体纤维化，缓解了SS的进展。

总之，这一研究提出，GRK2的基因敲除或药理学抑制显著减轻了腺体纤维化，缓解了SS的进展。GRK2与Smad2/3结合，并积极调节TGF-β-Smad信号的激活。TGF-β-GRK2正反馈回路有助于腺体纤维化。GRK2可能是治疗SS有前景的治疗靶点。

附：英文原文

Title: G protein-coupled receptor kinase 2 as a novel therapeutic target for gland fibrosis of Sjgren’s syndrome

Author: Fang, Ru-hong, Zhou, Zheng-wei, Chu, Rui, Guan, Qiu-yun, He, Feng, Ge, Ming-li, Guo, Pai-pai, Wu, Hua-xun, Yao, Ling-li, Wei, Wei, Ma, Yang, Wang, Qing-tong

Issue&Volume: 2024-07-25

Abstract: Sjogren’s syndrome (SS) is a chronic, progressive autoimmune disorder characterized by gland fibrosis. We previously found a close correlation between gland fibrosis and the expression of G protein-coupled receptor kinase 2 (GRK2). In this study we explored the pathological and therapeutic significance of GRK2 in SS. Submandibular gland (SMG) antigen-induced SS mouse model was established in WT and GRK2+/– mice. We showed that the expression levels of GRK2 were significantly up-regulated in glandular tissue and positively correlated with fibrotic morphology in SS patients and mice. Hemizygous knockout of GRK2 significantly inhibited the gland fibrosis. In mouse salivary gland epithelial cells (SGECs), we demonstrated that GRK2 interacted with Smad2/3 to positively regulate the activation of TGF-β-Smad signaling with a TGF-β-GRK2 positive feedback loop contributing to gland fibrosis. Hemizygous knockout of GRK2 attenuated TGF-β-induced collagen I production in SGECs in vitro and hindered gland fibrosis in murine SS though preventing Smad2/3 nuclear translocation. Around 28 days post immunization with SMG antigen, WT SS mice were treated with a specific GRK2 inhibitor paroxetine (Par, 5mg·kg1·d1, i.g. for 19 days). We found that Par administration significantly attenuated gland fibrosis and alleviated the progression of SS in mice. We conclude that genetic knockdown or pharmacological inhibition of GRK2 significantly attenuates gland fibrosis and alleviates the progression of SS. GRK2 binds to Smad2/3 and positively regulates the activation of TGF-β-Smad signaling. A TGF-β-GRK2 positive feedback loop contributes to gland fibrosis. Our research points out that GRK2 could be a promising therapeutic target for treating SS.

DOI: 10.1038/s41401-024-01350-4

Source: https://www.nature.com/articles/s41401-024-01350-4