Kidney Week

Abstract: SA-PO832

The Long Noncoding RNA Meg3 Mediates TLR4–Induced Renal Inflammation in Experimental Obstructive Nephropathy

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Yiu, Wai Han, The University of Hong Kong, Hong Kong, China

Wai Han Yiu,

• Wong, Dickson WL, The University of Hong Kong, Hong Kong, China

Dickson WL Wong,

• Lok, Wing yan, The University of Hong Kong, Hong Kong, China

Wing yan Lok,

• Liu, Wing han, The University of Hong Kong, Hong Kong, China

Wing han Liu,

• Li, Ye, The University of Hong Kong, Hong Kong, China

Ye Li,

• Chan, Loretta Y.Y., The University of Hong Kong, Hong Kong, China

Loretta Y.Y. Chan,

• Leung, Joseph C K, The University of Hong Kong, Hong Kong, China

Joseph C K Leung,

• Lai, Kar Neng, The University of Hong Kong, Hong Kong, China

Kar Neng Lai,

• Lan, Hui Y., The Chinese University of Hong Kong, Shatin, HONG KONG, China

Hui Y. Lan,

• Tang, Sydney C.W., The University of Hong Kong, Hong Kong, China

Sydney C.W. Tang,

Background

Renal inflammation has been implicated in many types of kidney injury and is a potential therapeutic target for most chronic kidney diseases. Accumulating evidence shows that long noncoding RNAs function as critical regulators of inflammatory responses. This study aims at investigating the role of Toll-like receptor 4 (TLR4)-driven lncRNAs in regulating renal inflammation.

Methods

Tubule-specific TLR4 knockout mice were generated by crossing TLR4 ^flox/flox and Ksp-Cre mice. Both Ksp-Cre.TLR4 ^flox/flox (KO) and TLR4 ^flox/flox (WT) mice were subjected to unilateral ureteral obstruction (UUO). Deep RNA sequencing was performed to identify dysregulated lncRNAs that are associated with tubular TLR4 expression. Candidate lncRNA was verified and its functional role in renal inflammation was investigated using cultured murine tubular epithelial cells.

Results

Loss of TLR4 in tubular cells resulted in less renal inflammation as compared to WT mice after 7 days of UUO. Expression of pro-inflammatory cytokines including CCL-2, CXCL-2 and TNF-α was reduced in the obstructed KO kidneys and accompanied by decreased NFκB signaling. Data from deep RNA sequencing showed that lncRNA maternally expressed gene 3 (Meg3) was upregulated in WT mice upon UUO, but its expression was down-regulated in KO mice. In vitro, LPS induced Meg3 expression in tubular epithelial cells. Knock down of Meg3 in tubular epithelial cells diminished inflammatory responses, as evidenced by reduced LPS-induced CCL-2 and CXCL-2 expression.

Conclusion

Our findings suggest that tubular TLR4 is important for mediating inflammatory responses in UUO model and lncRNA Meg3 may be a novel regulator in TLR4-driven renal inflammation.

Funding: Research Grants Council of Hong Kong (Collaborative Research Fund, grant number C7018-16G).