Abstract: PO1822
HMGB-1 Activates Mineralocorticoid Receptor-Dependent Endothelial Cell Injury via Receptor for Advanced Glycation End Products
Session Information
- Hypertension and CVD: Mechanisms
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Otsuka, Tomoyuki, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
- Ueda, Seiji, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
- Nagasawa, Hajime, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
- Okuma, Teruyuki, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
- Sato, Koji, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
- Matsui, Takanori, Kurume University Faculty of Medicine, Kurume-shi, Fukuoka, Japan
- Yamagishi, Sho-ichi, Showa University Faculty of Medicine, Shinagawa-ku, Tokyo, Japan
- Suzuki, Yusuke, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
Background
Endothelial dysfunction plays a central role in the pathogenesis of cardio-renal syndrome. High mobility group box-1 (HMGB-1) is a protein with various roles in different cellular compartments, and indirectly regulates the activity of transcription and DNA repair in the nucleus. On the other hand, during tissue damage, it is released into the extracellular environment as damage-associated molecular patterns (DAMPs). HMGB-1 is reported to elevate in CKD patients and be involved in endothelial dysfunction through binding to toll like receptor (TLR) and receptor for advanced glycation end products (RAGE). In addition, we recently demonstrated that RAGE-mediated Rac1 activated mineralocorticoid receptor (MR) and resulted in podocytes damage. In the present study, we hypothesized that crosstalk between HMGB-1/ RAGE and Rac1-MR pathways could contribute to endothelial dysfunction in kidney diseases.
Methods
In the present study, we investigated whether HMGB-1 could activate Rac1-MR axis and induce endothelial injury in cultured human umbilical vein endothelial cells (HUVECs) by assessing expression levels of genes for MCP-1 and cell adhesion factors (ICAM-1, VCAM-1) with or without administration of RAGE aptamer or MR blocker (esaxerenone, 1μM).
Results
HMGB-1 supplementation significantly increased GTP-bound Rac1 and enhanced MR translocation into the nucleus in HUVECs. We also found that RAGE expression was enhanced by HMGB-1 and RAGE aptamer completely abolished Rac1 activation and MR translocation observed in HMGB-1 exposed HUVECs. HMGB-1 also upregulated MCP-1, ICAM-1, and VCAM-1 in HUVECs, all of which were significantly blocked by pretreatment of RAGE aptamer as well as MR blocker.
Conclusion
These results suggest that there may be a close relationship between HMGB-1/ RAGE axis and Rac1/ MR activation, thus contributing endothelial injury. Using RAGE aptamer or MR blocker could be novel therapeutic strategies against endothelial dysfunction in patients with kidney diseases.