Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK-p90RSK, and Rho-kinase pathway.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cepsilon (PKCepsilon) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, -61%; 30 mg, -78%; and 100 mg, -84% versus DS; P<0.01, respectively) and urinary protein (10 mg, -78%; 30 mg, -87%; and 100 mg, -88% versus DS; P<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKCepsilon-MAP kinase-p90RSK pathway, and improvement in endothelial function.
Kobayashi
Naohiko
N
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. nao-koba@dokkyomed.ac.jp
Hara
Kazuyoshi
K
Tojo
Akihiro
A
Onozato
Maristela Lika
ML
Honda
Takeaki
T
Yoshida
Kohtaro
K
Mita
Shin-ichiro
S
Nakano
Shigefumi
S
Tsubokou
Yusuke
Y
Matsuoka
Hiroaki
H
D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D019610:Cytoprotection; D000077545:Eplerenone; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000473:pathology; D006973:Hypertension / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051744:Protein Kinase C-epsilon; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011507:Proteinuria / Q000209:etiology / Q000503:physiopathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D020303:Rats, Inbred Dahl; D011973:Receptors, LDL / Q000037:antagonists & inhibitors*; D051131:Receptors, Oxidized LDL; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors; D051127:Scavenger Receptors, Class E; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D054460:rho-Associated Kinases
D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D000451:Mineralocorticoid Receptor Antagonists; C495136:OLR1 protein, rat; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D013148:Spironolactone; D000077545:Eplerenone; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C497257:Prkce protein, rat; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases