Long non-coding RNA Neat1 promotes acute kidney disease via activation of NLRP3 inflammasome

Abstract Acute kidney injury (AKI) is common in hospitalized patients and is associated with high mortality. Inflammation plays a key role in the pathophysiology of AKI. Long non-coding RNAs (lncRNAs) are being increasingly recognized as regulators of the inflammatory and immune response. In this study, we first observed significantly increased urinary and circulating lncRNA Neat1 among 66 hospitalized patients with AKI versus control subjects from a primary care clinic; and among kidney transplant recipients, Neat1 levels were highest after surgery followed by a prompt decline to normal levels in parallel with recovery of kidney function. Next, in a mouse model of lipopolysaccharide (LPS)-induced septic AKI, in which kidney tubular Neat1 was increased, short hairpin RNA-mediated knockdown of Neat1 in the kidney preserved kidney function by lowering BUN and serum creatinine/cystatin C, protected against tubular apoptosis and suppressed overexpression of AKI biomarkers KIM-1 and NGAL, leukocyte infiltration and both intrarenal and systemic inflammatory cytokines IL-6, TNF-α and IL-1β. Finally, in LPS-treated C1.1 mouse kidney tubular cells, Neat1 was induced via the TLR4/NF-κB signaling pathway which promoted subsequent activation of NLRP3 inflammasomes via binding with another scaffold protein, Rack1. Silencing of Neat1 in C1.1 cells ameliorated LPS-induced upregulation of IL-6, whereas overexpressing Neat1 alone without LPS stimulation was sufficient to drive C1.1 cells into a proinflammatory phenotype. In conclusion, Neat1 exerts a prominent role in AKI by promoting NLRP3 inflammasome activation and is a potential novel biomarker and therapeutic target for AKI.