LncRNA Antisense Noncoding RNA in the INK4 Locus (ANRIL) Mediates Endothelial Dysfunction Through Brain-Derived Neurotrophic Factor Downregulation in CKD
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
- Su, Hong, Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Lv, Zhimei, Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Wang, Rong, Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
Cardiovascular risk is increased in chronic kidney disease (CKD), endothelial dysfunction is the earliest phenomena of cardiovascular diseases, which could be induced by accumulation of uremic toxins in CKD. long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) has been reported to be associated with a variety of vascular disease. And evidence also suggested that it may be involved in the occurrence and development of vascular disease in CKD.
The endothelial function in adult patients with CKD were evaluated and plasma ANRIL levels were measured. C57Bl/6J wild type or ANRIL knockout mice subjected to CKD were used to evaluate the role of ANRIL in vascular endothelial injury in vivo. Meanwhile, endothelial cells were incubated with serum derived from CKD patients and uremia toxins, then ANRIL expression was detected and the proteins that interact with ANRIL were explored. By making use of the gain- and loss-of-function approaches, ANRIL biological function and underlying mechanism were confirmed.
In humans, the circulating ANRIL levels were increased and correlated with vascular endothelial dysfunction in patients with CKD, also negatively correlated with plasma brain-derived neurotrophic factor (BDNF) concentration. Then we found that ANRIL deficiency reversed the endothelial dysfunction and relative BDNF abnormal expression in CKD mice. In addition, serum derived from CKD patients and uremia toxins induced ANRIL upregulation in endothelial cells, and ANRIL mediated endothelial dysfunction through BDNF downregulation. Mechanically, we verified the binding of ANRIL to histone methyltransferase Enhancer of zeste homolog 2 (EZH2). Further experiments found increased EZH2 and histone H3 lysine 27 trimethylation levels at the BDNF promoter region. Collectively, we demonstrated that ANRIL mediate BDNF transcriptional suppression through recruitment of EZH2 to the BDNF promoter region, then regulated the proteins expression related to endothelial function.
In the present study, we provide the evidence that ANRIL were associated with endothelial dysfunction in CKD, and ANRIL mediated endothelial dysfunction through BDNF downregulation. This may provide a new theoretical basis for the occurrence and development of endothelial dysfunction in CKD.
- Government Support – Non-U.S.