The long noncoding RNA Meg3 mediates TLR4-induced inflammation in experimental obstructive nephropathy

Area of Science:

• Nephrology
• Molecular Biology
• Immunology

Background:

• Kidney inflammation drives chronic kidney disease (CKD) progression.
• Toll-like receptor 4 (TLR4) signaling is implicated in kidney inflammation, but its regulatory mechanisms in tubular injury remain unclear.

Purpose of the Study:

• To investigate the role of long noncoding RNA (lncRNA) Meg3 in TLR4-mediated kidney inflammation and fibrosis.
• To elucidate the regulatory pathway involving Meg3 in tubular epithelial cells during kidney injury.

Main Methods:

• Utilized tubule-specific TLR4 knockout mice to study obstruction-induced kidney injury.
• Performed transcriptome analysis to identify differentially expressed lncRNAs.
• Investigated Meg3 induction by lipopolysaccharide (LPS) in tubular epithelial cells via a p53-dependent pathway.
• Assessed the effects of Meg3 silencing on inflammatory responses and kidney fibrosis in vitro and in vivo.

Main Results:

• Tubule-specific deletion of TLR4 protected against kidney injury, reducing inflammation, macrophage infiltration, and fibrosis.
• lncRNA Meg3 was significantly downregulated in the kidneys of TLR4 knockout mice.
• Meg3 expression was induced by LPS in tubular cells through p53 signaling.
• Meg3 silencing attenuated LPS-induced cytokine production (CCL-2, CXCL-2) and p38 MAPK activation, and ameliorated kidney fibrosis.

Conclusions:

• lncRNA Meg3 plays a pro-inflammatory role in the progression of chronic kidney disease.
• A novel regulatory pathway involving TLR4, p53, and Meg3 in tubular epithelial cells contributes to kidney inflammation and fibrosis.
• Targeting lncRNA Meg3 represents a potential therapeutic strategy for TLR4-driven kidney diseases.