title: Ceramide Production Mediates Aldosterone-Induced Human Umbilical Vein Endothelial Cell (HUVEC) Damages.
abstract: Here, we studied the underlying mechanism of aldosterone (Aldo)-induced vascular endothelial cell damages by focusing on ceramide. We confirmed that Aldo (at nmol/L) inhibited human umbilical vein endothelial cells (HUVEC) survival, and induced considerable cell apoptosis. We propose that ceramide (mainly C18) production might be responsible for Aldo-mediated damages in HUVECs. Sphingosine-1-phosphate (S1P), an anti-ceramide lipid, attenuated Aldo-induced ceramide production and following HUVEC damages. On the other hand, the glucosylceramide synthase (GCS) inhibitor PDMP or the ceramide (C6) potentiated Aldo-induced HUVEC apoptosis. Eplerenone, a mineralocorticoid receptor (MR) antagonist, almost completely blocked Aldo-induced C18 ceramide production and HUVEC damages. Molecularly, ceramide synthase 1 (CerS-1) is required for C18 ceramide production by Aldo. Knockdown of CerS-1 by targeted-shRNA inhibited Aldo-induced C18 ceramide production, and protected HUVECs from Aldo. Reversely, CerS-1 overexpression facilitated Aldo-induced C18 ceramide production, and potentiated HUVEC damages. Together, these results suggest that C18 ceramide production mediates Aldo-mediated HUVEC damages. MR and CerS-1 could be the two signaling molecule regulating C18 ceramide production by Aldo.
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Peihua
authors.initials: P
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Shijian
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Huiyi
authors.initials: H
authors.lastname: Gu
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Guo
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Hu
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D002518:Ceramides / Q000096:biosynthesis* / Q000235:genetics; D000077545:Eplerenone; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002518:Ceramides; D008246:Lysophospholipids; D008565:Membrane Proteins; C060506:sphingosine 1-phosphate; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; C493790:CERS1 protein, human; D051049:Sphingosine N-Acyltransferase; D013110:Sphingosine