PS-B08-6: ROLE OF THE HMGB-1/RAGE AXIS AND MINERALOCORTICOID RECEPTOR IN THE PATHOGENESIS OF ACUTE KIDNEY INJURY

Abstract

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 elevated in the pathogenesis of acute kidney injury (AKI) 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 subsequently 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 AKI. Methods: In the present study, we performed a renal ischemia-reperfusion model (I/R group) on C57BL/6J mice to evaluate the expression of Rac1-MR pathway and organ damage. In addition, the I/R group was pretreated with MR blocker (esaxerenone) and evaluated in the same way. In vitro study, we investigated whether HMGB-1 could activate Rac1-MR axis and thus induce endothelial injury in cultured human umbilical vein endothelial cells (HUVECs) by assessing expression levels of genes for MCP-1 and NF-κB with or without administration of RAGE aptamer or MR blocker. Results: In the I/R group, MR activation assessed by translocation into the nucleus and enhanced RAGE expression were observed along with HMGB-1 and RAGE elevation, and pretreatment with MR blocker suppressed the elevation of serum creatinine levels as well as tubular necrosis. Further, the loss of peritubular capillaries observed in I/R kidney was markedly suppressed by MR blocker. In vitro study, HMGB-1 supplementation significantly increased RAGE expression, GTP-bound Rac1 and enhanced MR translocation into the nucleus in HUVECs as well. We also found that HMGB-1 upregulated MCP-1 and NF-κB, all of which were significantly blocked by pretreatment of RAGE aptamer and 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 AKI.