Abstract
OBJECTIVES AND DESIGN: In this study, we examined the role of MALAT1, a highly conserved nuclear long non-coding RNA molecule, in chronic diabetic complications affecting the heart and kidneys using both in vitro and in vivo models: human endothelial cell culture and a Malat1 knockout mice model. RESULTS: Findings from our in vitro experiments demonstrated that MALAT1 was predominantly localized to nuclear speckles in endothelial cells and MALAT1 expression was significantly increased following incubation with high glucose in association with increased expression of inflammatory cytokines. As for our in vivo experiments, we used Malat1 knockout mice and wild-type controls with or without streptozotocin-induced diabetes over 2 months of follow-up, where all of our diabetic animals showed hyperglycaemia and polyuria. Examination of cardiac and renal tissues demonstrated altered MALAT1 RNA expression in wild-type diabetic animals. Such changes were associated with augmented production of downstream inflammatory molecules at the mRNA and protein levels. Diabetes-induced elevations of inflammatory markers were significantly decreased in Malat1 knockout diabetic animals. In addition to transcript and protein analyses, we examined functional changes in the heart and kidneys. Organ functions were affected in the wild-type diabetic mice but were rescued in Malat1 knockout mice. CONCLUSIONS: Taken together, findings from this study will provide direct evidence and insight into the importance of MALAT1 in the pathogenesis of chronic diabetic complications involving the heart and kidneys.