ABSTRACT
The gastrin-releasing peptide receptor (GRPR) binds to ligands such as gastrin-releasing peptide (GRP) and plays a variety of biological roles. In this study, we investigated the therapeutic effect of a novel gastrin-releasing peptide receptor antagonist RH-1402 in hyperuricemia-induced kidney fibrosis and its underlying mechanisms. We conducted enzyme linked immunosorbent assay (ELISA) and immunohistochemical analyses and found that proGRP and GRPR expression levels were significantly increased in patients with hyperuricemic nephropathy (HN) and HN mice. GRPR knockdown significantly attenuated inflammatory and fibrotic responses in adenosine-treated human proximal tubule epithelial cells. GRPR knockout or GRPR conditional knockout in renal tubular epithelial cells significantly alleviated the decline in renal function and fibrosis in HN mice in vivo. RNA-seq and String database analysis revealed that GRP/GRPR promoted HN by suppressing the ABCG2/PDZK1 and increasing TGF-ß/Smad3 levels by activating the NF-κB pathway. Overexpression of GRPR increased TGF-ß/Smad3 levels, where as it reduced ABCG2/PDZK1 levels in adenosine-treated HK2 cells, which was reversed by the NF-κB inhibitor. Furthermore, we evaluated the therapeutic effects of the novel GRPR inhibitor RH-1402 on hyperuricaemia-induced renal injury and evaluated the inflammatory and fibrosis responses in vivo and in vitro. Pre-treatment with RH-1402 attenuated hyperuricaemia-induced renal injury, restored renal function, and suppressed renal inflammation and fibrosis. Taken together, GRPR enhances hyperuricaemia-induced tubular injury, inflammation, and renal fibrosis via ABCG2-dependent mechanisms and may serve as a promising therapeutic target for HN treatment.
Subject(s)
Hyperuricemia , Kidney Diseases , Nephritis , Animals , Humans , Mice , Adenosine , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Fibrosis , Hyperuricemia/drug therapy , Inflammation , Kidney Diseases/etiology , Neoplasm Proteins/metabolism , Nephritis/etiology , NF-kappa B/metabolism , Receptors, Bombesin/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolismABSTRACT
The manufacturing of 3D and conformal metamaterials remains a major challenge. The projection micro-stereolithography 3D printing technology combined with the liquid metal filling method is employed here to fabricate the metamaterials, which are characterized with embedded features that can effectively protect the metal resonance layer from external influence, and integrated molding of macro-micro structures and function-structure. To demonstrate the robustness and flexibility of the proposed method, three types of metamaterials are fabricated: 3D orthogonal split-ring resonator metamaterial, bionic compound eye conformal metamaterial, and a five-layer broadband conformal metamaterial in the form of hemispherical moth-eye, which are costly, tedious, and time consuming in conventional fabrication methods. And the layout of the filling channel is optimized and the polydimethylsiloxane coating post-treatment process is applied to smooth the surface roughness caused by the staircase effect of 3D printing to improve the transmission performance of metamaterial devices. The transmission properties are measured using terahertz time-domain spectroscopy system and the experimental results show that the method proposed in this paper makes metamaterial manufacture no longer limited to complex structures, which effectively expands the application range of metamaterials.
