The functional role of LncRNA Neat1 in the kidney

Abstract

In recent years, the prevalence of kidney disease is increasing, which has become one of the important reasons threatening human health. It gradually progresses to end-stage renal disease (ESRD) at a later stage and becomes a major economic burden, so there is an urgent need to discover new detection and prevention methods. Non-coding RNAs have been found to play an important role in various physiological and pathological processes. Long non-coding RNA nuclear enriched abundant transcript 1 (Neat1) not only serves as a key structural component of nuclear paraspeckle, it is also involved in a variety of pathophysiological processes. Here, I investigate whether Neat1 plays a role in acute kidney injury (AKI) and diabetic kidney disease (DKD). This study mainly explores the role of Neat1 in kidney diseases from three aspects. In human, from a cross-sectional cohort, circulating and urinary Neat1 level was highly induced in patients with AKI compared to control subjects, 1 respectively, after adjusting for baseline eGFR and comorbidities; from the longitudinal study, recipients who underwent kidney transplantation showed that longitudinally high post-operative Neat1 levels gradually declined in parallel with the recovery of allograft kidney function following surgery to levels comparable to those in non-AKI subjects. Furthermore, kidney Neat1 expression was increased significantly in kidney biopsies of DKD patients compared with control subjects and other kidney diseases. For animal studies, Neat1 was induced in sepsis- induced AKI mouse kidney and streptozotocin (STZ)-induced diabetic kidney while its expression was markedly suppressed following microbubble gene transfer with shRNA Neat1 plasmids to specific knock down Neat1 in kidney, respectively. Both sepsis-induced AKI kidney and STZ-induced diabetic kidney showed that knockdown of Neat1 attenuated tubular injury and reduced renal inflammation. For STZ- induced DKD mice, they also showed knockdown of Neat1 attenuated renal fibrosis in tubular, and mesangial expansion, podocytes injury in glomerular. In vitro, expression of Neat1 was increased significantly in LPS/nigericin treated and high glucose treated tubular epithelial C1.1 cells, respectively. Furthermore, expression of Neat1 was regulated by TLR4/NF-κB signaling in LPS/nigericin treated and high glucose treated tubular epithelial C1.1 cells, respectively. Mechanistically, Neat1 regulates the occurrence and progression of sepsis-related tubular cell 2 injury by affecting NLRP3 inflammasome. In detail, Neat1 promoted the activation of NLRP3 inflammasome through its protein partner Rack1 in LPS/nigericin treated tubular epithelial C1.1 cells. Besides, I also identified the protein partner hnRNPA1, which is closely related to IL-6 expression in high glucose treated tubular epithelial C1.1 cells. And I further found that the changes of Neat1 and protein partner hnRNPA1 affects the Stat3 signaling, which is the classic downstream of IL-6 in high glucose treated tubular epithelial C1.1 cells. Overall, this evidence suggest that increased Neat1 expression contributes to the pathogenesis of AKI and DKD and targeting Neat1 may be a novel and potential therapeutic strategy for kidney injury