Int J Med Sci 2023; 20(6):810-817. doi:10.7150/ijms.78279 This issue Cite
1. School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University; Department of Medical Research, Chung Shan Medical University Hospital, 110 Jianguo North Road, Section 1, Taichung 40203, Taiwan, ROC.
2. Department of Internal Medicine, China Medical University Beigang Hospital, 123 Sinde Road, Beigang Township, Yunlin County, 65152, Taiwan, ROC.
3. School of Chinese Medicine, College of Chinese Medicine, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC.
4. Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
5. Department of Respiratory Therapy, China Medical University Beigang Hospital, 123 Sinde Road, Beigang Township, Yunlin County, 65152, Taiwan, ROC.
6. Institute of Medicine, Chung Shan Medical University, 110 Jianguo North Road, Section 1, Taichung 40203, Taiwan, ROC.
*These authors contributed equally to this work.
Interferon gamma (IFNγ) is a cytokine implicated in the pathogenesis of autoimmune diseases. SAM and HD domain-containing protein 1 (SAMHD1) is an IFNγ-inducible protein that modulates cellular dNTP levels. Mutations in the human SAMHD1 gene cause Aicardi-Goutières (AG) syndrome, an autoimmune disease sharing similar clinical features with systemic lupus erythematosus (SLE). Klotho is an anti-inflammatory protein which suppresses aging through multiple mechanisms. Implication of Klotho in autoimmune response is identified in rheumatologic diseases such as SLE. Little information exists regarding the effect of Klotho in lupus nephritis, one of the prevalent symptoms of SLE. The present study verified the effect of IFNγ on SAMHD1 and Klotho expression in MES-13 glomerular mesangial cells, a special cell type in glomerulus that is critically involved in lupus nephritis. IFNγ upregulated SAMHD1 expression in MES-13 cells through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT1) and the nuclear factor kappa B (NFκB) signaling pathways. IFNγ decreased Klotho protein expression in MES-13 cells. Treatment of MES-13 cells with recombinant Klotho protein inhibited SAMHD1 expression by blocking IFNγ-induced NFκB nuclear translocation, but showed no effect on JAK-STAT1 signaling. Collectively, our findings support the protective role of Klotho in attenuating lupus nephritis through the inhibition of IFNγ-induced SAMHD1 expression and IFNγ downstream signaling in MES-13 cells.
Keywords: IFNγ, SAMHD1, Klotho, glomerular mesangial cells, NFκB, JAK-STAT1