LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Nephrology

Background:

• Endothelial dysfunction is prevalent in chronic kidney disease (CKD) but its underlying mechanisms remain unclear.
• Circulating ANRIL levels are elevated in CKD patients and correlate with endothelial dysfunction and reduced brain-derived neurotrophic factor (BDNF).

Purpose of the Study:

• To elucidate the mechanism by which ANRIL contributes to endothelial dysfunction in CKD.
• To investigate the role of ANRIL-BDNF interaction in regulating endothelial function and mitochondrial dynamics.

Main Methods:

• ANRIL knockout mice models were used to assess the impact of ANRIL deficiency on endothelial markers and mitochondrial proteins.
• In vitro studies utilized serum from CKD patients and uremic toxins to induce ANRIL expression.
• RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assays identified ANRIL's interaction with EZH2.
• Chromatin immunoprecipitation (ChIP) analyzed EZH2 and H3K27me3 enrichment at the BDNF promoter.

Main Results:

• ANRIL deficiency in mice reversed abnormal expression of BDNF, eNOS, VCAM-1, vWF, Drp1, and Mfn2.
• CKD patient serum and uremic toxins increased ANRIL expression in vitro.
• ANRIL directly binds to EZH2, leading to increased H3K27me3 at the BDNF promoter, thus suppressing BDNF transcription.
• Gain- and loss-of-function studies confirmed ANRIL mediates endothelial dysfunction via BDNF downregulation.

Conclusions:

• ANRIL promotes endothelial dysfunction in CKD by transcriptionally suppressing BDNF through EZH2 recruitment.
• This pathway affects proteins critical for endothelial function and mitochondrial dynamics, offering novel therapeutic targets for CKD-related vascular complications.