Heterozygous Gnaq deficiency enhances Ifi202b/IFI16 and NF-κB activation in endothelial cells and exacerbates lupus nephritis pathology
Lu Zhang,
Yan He,
Mengqin Zhang,
Jimin Zhang,
Wuwei Zhuang,
Yuechi Sun,
Xing Chen,
Hangzhou Fu,
Xuanli Tang,
Guixiu Shi
Affiliations
Lu Zhang
Department of Nephrology (Fujian Provincial Clinical Research Center for Glomerular Nephritis), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Corresponding author
Yan He
Department of Rheumatology and Clinical Immunology (Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen Key Laboratory of Rheumatology and Clinical Immunology), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Mengqin Zhang
Department of Rheumatology and Clinical Immunology (Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen Key Laboratory of Rheumatology and Clinical Immunology), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
Jimin Zhang
Department of Rheumatology and Clinical Immunology (Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen Key Laboratory of Rheumatology and Clinical Immunology), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Wuwei Zhuang
Department of Rheumatology and Clinical Immunology (Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen Key Laboratory of Rheumatology and Clinical Immunology), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Yuechi Sun
Department of Rheumatology and Clinical Immunology (Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen Key Laboratory of Rheumatology and Clinical Immunology), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Xing Chen
Department of Nephrology (Fujian Provincial Clinical Research Center for Glomerular Nephritis), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Hangzhou Fu
Department of Pathology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
Xuanli Tang
Department of Nephrology (Key Laboratory of Zhejiang Province, Management of Kidney Disease), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
Guixiu Shi
Department of Rheumatology and Clinical Immunology (Xiamen Municipal Clinical Research Center for Immune Diseases, Xiamen Key Laboratory of Rheumatology and Clinical Immunology), The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Corresponding author
Summary: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), exhibits significant heterogeneity. Recent evidence suggests that non-immune factors contribute to end-organ damage, challenging the traditional view of LN solely arising from immune dysregulation. To investigate this, we employed autoimmune-prone Gnaq+/− mice receiving intraperitoneal pristane injections. Bone marrow transfer (BMT) distinguished the roles of immune versus non-immune cells. We observed that: (1) BMT from wild-type (WT) mice to Gnaq+/− recipients resulted in severe proteinuria and diffuse proliferative nephritis after pristane exposure; (2) GNAQ knockdown increased the expression of IFI16/Ifi202b and activated the NF-κB pathway in endothelial cells; and (3) increased IFI16 expression in human kidney biopsies correlated with proliferative LN. Taken together, these findings suggest that GNAQ acts as an inflammatory regulator in kidney endothelial cells via the IFI16/NF-κB pathway, potentially linking it to the development of LN in humans.
