PS-B03-10: EPLERENONE INHIBITS ICAM-1 FROM MACROPHAGES AND MACROPHAGE-TO-MYOFIBROBLAST TRANSITION IN TYPE 4 CARDIORENAL SYNDROME RATS INDUCED WITH UUO

Abstract

Objective: The type 4 cardiorenal syndrome (CRS) represents the kidney-heart relationship in a pathological situation where cardiovascular complications dominate all causes of death in patients with chronic kidney disease (CKD), but the underlying mechanism of CKD-induced cardiac disease have not been fully clarified. We reported that aldosterone directly stimulates cardiac fibrosis, whereas macrophage-to-myofibroblast (MMT) is associated with fibrosis. However, the mechanistic basis of this pathogenic pathway that promotes cardiac fibrosis remains to be elucidated. Design and method: We used a 180-day rat model of unilateral ureteral obstruction (UUO) to replicate the CRS model and RAW264.7 cells in-vitro studies. Using eplerenone, a blocker of mineralocorticoid receptor (MR), to test the effect of aldosterone in cardiac fibrosis induced by UUO. The levels of intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP)-1 were examined to verify the role of macrophage infiltration and inflammatory injury. Co-expression of macrophage marker CD68 and myofibroblast marker -SMA to identify MMT contributing to cardiac fibrosis. Results: We identified cardiac injury in UUO rats, and eplerenone can inhibit UUO-induced cardiac fibrosis. We found that macrophages can co-express the myofibroblast marker alpha-SMA for phenotypic transformation and participate in cardiac fibrosis by secreting collagen III, while eplerenone inhibits this process. Activated MR enhanced macrophage infiltration and secretion of ICAM-1 and MCP-1, which stimulated inflammatory injury in the heart, whereas aldosterone stimulation and eplerenone treatment with RAW264.7 revealed a role for aldosterone in cardiac fibrosis. Conclusions: Our results identified the role of aldosterone in promoting macrophage infiltration and MMT through MR/SGK-1 pathway. These findings provide a new mechanism for macrophage involvement in the pathogenesis of UUO-induced cardiac fibrosis and reveal novel therapeutic targets.