PS-B12-1: EPLERENONE INHIBITS UUO-INDUCED LYMPHANGIOGENESIS AND CARDIAC FIBROSIS BY ATTENUATING INFLAMMATORY INJURY. (January 2023)

• Record Type: Journal Article
• Authors: Chen, Gege; Chang, Yi; Yang, Fan; Wang, Xiangting; Shimosawa, Tatsuo; Xu, Qingyou
• Is Part Of: Journal of hypertension. Volume 41(2023)Supplement 1
• Page Start: e453
• Publication Date: 2023-01
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000917492.48464.e4
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: Cardiorenal syndrome (CRS) is the leading cause of death associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), however, the underlying mechanism of CKD-induced cardiac injury is incompletely understood. We reported that aldosterone is associated with cardiac fibrosis, and that inflammatory injury and lymphangiogenesis are involved. This pathogenic mechanism CKD-induced cardiac fibrosis still needs further investigation. Design and method: The unilateral ureteral obstruction (UUO) model was used to replicate the CRS type 4 model. Following induction of renal injury, the rats received eplerenone for 180-day. For in-vitro studies, we exposed human lymphatic endothelial cells (hLEC) to aldosterone and eplerenone. Changes in cardiac tissue related to lymphangiogenesis and inflammatory were analyzed in vivo. Changes in lymphangiogenesis, LEC phenotypic transformation and activation of mineralocorticoid receptor (MR)/ transforming growth factor (TGF)-beta/ vascular endothelial growth factor C (VEGFC) signaling axis involved in these changes were analyzed in vivo and in vitro. Results: We found that eplerenone ameliorated cardiac inflammation and fibrosis in UUO rats. Moreover, eplerenone inhibited MR activation, attenuated lyphangiogenesis and LEC phenotypic transformation, and regulated TGF-beta/CTGF/VEGFC signaling axis in vivo and in vitro. The levels of podoplanin, VEGFR-3 and VEGFC confirmed the role of lymphangiogenesis and inflammatory injury. Co-expression of LEC marker LYVE-1 and myofibroblast marker alpha-SMA validated EndMT in cardiac fibrosis. Treatment with eplerenone, clarified the role of aldosterone in UUO-induced cardiac fibrosis. Conclusions: We confirmed that eplerenone can alleviate UUO-induced cardiac fibrosis by inhibiting inflammation and lymphangiogenesis via MR/TGF-beta/VEGFC signaling axis. These findings provide an in-depth understanding of pathogenesis of UUO-induced cardiac injury and reveal novel therapeutic targets.