AB0198 THE ROLE OF LOW EXPRESSION OF MIR-127–3P IN THE PATHOGENESIS OF LUPUS NEPHRITIS

Background Lupus nephritis (LN) is one of the most severe organ lesions in systemic lupus erythematosus (SLE). Overactivation of the type I interferon (IFN-I) signaling pathway is associated with the pathogenesis of LN. Overexpression of the IFN stimulated genes (ISGs) was found in the kidneys of LN patients, and the absence of the IFN receptor reduced nephritis in lupus prone mice. Abnormal expression of microRNA in renal tissue is involved in the pathogenesis of LN. Objectives We aimed to investigate the role of renal microRNA related to LN in the over-activation of the IFN signaling pathway of LN kidney. Methods The expression of microRNA was determined by Taqman method. Interferon stimulation response element (ISRE) -luciferase reporter gene assay and western blot assay were used to study the function of candidate microRNA in IFN signal transduction pathway. mRNA expression was measured by SYBR green method. Gene expression profile was detected by gene expression microarray. Antagomir and Agomir (chemically modified microRNA mimics and antagomir inhibitors) of candidate microRNAs were used for functional gain and functional loss experiments. Results Among differentially expressed renal microRNAs in LN, miR-127-3p was reduced in renal tissues of patients with LN. The miR-127-3p suppressed the fluorescase gene expression of ISRE induced by ISRE, and the phosphorylation of STAT1 and STAT2. By microarray analysis, we found that most ISG was inhibited by miR127-3p in IFN-stimulated Hela cells. The functional deletion of miR-127-3p enhanced the IFN response in human primary mesangial cells, which was manifested by enhanced ISRE mediated reporter gene expression, enhanced STAT2 phosphorylation and increased ISG expression. In addition, we found that JAK1, the upstream tyrosine kinase of STAT1 and STAT2, was a new target molecule for miR-127-3p. Conclusion Our study shows that miR-127-3p can inhibit IFN signal transduction by targeting JAK1. The decreased expression of miR-127-3p in the kidney is associated with an overactive IFN response in the renal tissue of patients with LN. Subsequent mouse model studies indicate the therapeutic potential of miR-127-3p in treating lupus associated organ damage. References [1] Han X, Wang Y, Zhang X, et al. MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I InterferonPathway on Renal Mesangial Cells. Arthritis Rheumatol. 2016 Sep;68(9):2232-43. [2] Wu L, Qin Y, Xia S, et al. Identification of Cyclin-Dependent Kinase 1 as a Novel Regulator of Type I Interferon Signaling in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2016 May;68(5):1222-32. Disclosure of Interests None declared