#2052 Reciprocal interplay between miR-155-5p and SOCS1 in the development of renal and vascular damage in experimental diabetes

Abstract

Abstract Background and Aims Chronic kidney disease and atherosclerosis are common vascular complication of diabetes and a global health issue. Hyperglycemia, dyslipidemia, and cytokines activate Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway to induce mediators of inflammation and oxidative stress, which are critical events in the progression of renal and vascular damage in diabetic patients. MicroRNAs are small, non-coding molecules and key regulators of gene expression. There is evidence of microRNA-155 (miR-155) involvement in diabetes complications, but the underlying mechanisms are unclear. In this study, gain- and loss-of-function experiments were applied to investigate the interplay between miR-155-5p and suppressor of cytokine signaling 1 (SOCS1) in the regulation of JAK/STAT pathway during renal and vascular injury in diabetes. Method Mesangial, tubuloepithelial, and vascular smooth muscle cells were transfected with miR-155-5p mimic or inhibitor, SOCS1 expression plasmid or siRNA, before stimulation with cytokines or high-glucose. Apolipoprotein E deficient mice with streptozotocin-induced diabetes were treated with either SOCS1-encoding adenovirus or miR-155-5p inhibitor. Samples were analyzed for the expression of miR-155-5p, SOCS1, and mediators of renal and vascular damage. Results In diabetic mice, the expression of miR-155-5p correlated inversely with SOCS1 levels and positively with markers of renal dysfunction, atherosclerosis, inflammation and oxidative stress. In renal cells, transfection with miR-155-5p mimic downregulated SOCS1, activated STAT1 and cytokine expression, and stimulated cell proliferation and migration. Mimic transfection also promoted the transition from contractile to synthetic phenotype in vascular smooth muscle cells. Conversely, both miR-155-5p antagonism and SOCS1 overexpression protected cells from inflammatory damage. In vivo SOCS1 gene delivery in diabetic mice decreased miR-155-5p and prevented kidney and vascular injury. Finally, therapeutic inhibition of miR-155-5p alleviates albuminuria, renal inflammation and fibrosis in diabetic mice, and also reduced atherosclerosis burden and improved plaque stability. Conclusion The modulation of miR-155/SOCS1 axis protects against diabetic renal and vascular damage in mice, thus highlighting its potential as therapeutic target for chronic complications of diabetes.