2. Academic Validation
  3. G protein-coupled receptor kinase 2 as a novel therapeutic target for gland fibrosis of Sjögren's syndrome

G protein-coupled receptor kinase 2 as a novel therapeutic target for gland fibrosis of Sjögren's syndrome

  • Acta Pharmacol Sin. 2024 Jul 25. doi: 10.1038/s41401-024-01350-4.
Ru-Hong Fang # 1,  Zheng-Wei Zhou # 1 2,  Rui Chu 1,  Qiu-Yun Guan 1,  Feng He 1,  Ming-Li Ge 1,  Pai-Pai Guo 1,  Hua-Xun Wu 1,  Ling-Li Yao 3,  Wei Wei 4,  Yang Ma 5,  Qing-Tong Wang 6 7
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China.
  • 2 Department of Pharmacy, Lu'an Hospital of Anhui Medical University, Lu'an People's Hospital of Anhui Province, Lu'an, 237006, China.
  • 3 Department of Pathology, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, 230001, China.
  • 4 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China. wwei@ahmu.edu.cn.
  • 5 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China. mayang@ahmu.edu.cn.
  • 6 Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China. qingtongwang@ahmu.edu.cn.
  • 7 The Third Affiliated Hospital of Anhui Medical University (the First People's Hospital of Hefei), Hefei, 230061, China. qingtongwang@ahmu.edu.cn.
  • # Contributed equally.
PMID: 39054339 DOI: 10.1038/s41401-024-01350-4
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, 5 mg·kg-1·d-1, 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.

Keywords

GRK2; SGECs; Sjögren’s syndrome; Smad2/3; gland fibrosis; paroxetine.

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