on February 14, 2005
Published online before print February 14, 2005, doi: 10.1161/01.HYP.0000157408.43807.5a
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 22, 2004
From the Department of Hypertension and Cardiorenal Medicine (N.K., K.H., T.H., K.Y., S.M., S.N., Y.T., H.M.), Dokkyo University School of Medicine, Tochigi, Japan; and the Division of Nephrology and Endocrinology (A.T., M.L.O.), University of Tokyo, Tokyo, Japan. * To whom correspondence should be addressed. E-mail: nao-koba{at}dokkyomed.ac.jp.
Abstract--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 C
Revised on October 20, 2004
Eplerenone Shows Renoprotective Effect by Reducing LOX-1-Mediated Adhesion Molecule, PKC
Naohiko Kobayashi*; 
-MAPK-p90RSK, and Rho-Kinase Pathway
(PKC) 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 PKC, 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 PKC-MAP kinase-p90RSK pathway, and improvement in endothelial function.
Key words: aldosterone • hypertension • oxidative stress
This article has been cited by other articles:
 |
|
 |
|
  V. Ramirez, J. Trujillo, R. Valdes, N. Uribe, C. Cruz, G. Gamba, and N. A. Bobadilla Adrenalectomy prevents renal ischemia-reperfusion injury Am J Physiol Renal Physiol, October 1, 2009; 297(4): F932 - F942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Klanke, N. Cordasic, A. Hartner, R. E. Schmieder, R. Veelken, and K. F. Hilgers Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension Nephrol. Dial. Transplant., November 1, 2008; 23(11): 3456 - 3463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-S. Zhou, I. H. Schuman, E. A. Jaimes, and L. Raij Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-{beta}, and fibronectin with concomitant increase in nitric oxide bioavailability Am J Physiol Renal Physiol, July 1, 2008; 295(1): F53 - F59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Sun, M. Bello-Roufai, and X. Wang RNAi inhibition of mineralocorticoid receptors prevents the development of cold-induced hypertension Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1880 - H1887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Ortiz, M. L. Graciano, J. J. Mullins, and K. D. Mitchell Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1584 - F1591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Ortiz, M. L. Graciano, D. Seth, M. S. Awayda, and L. G. Navar Aldosterone receptor antagonism exacerbates intrarenal angiotensin II augmentation in ANG II-dependent hypertension Am J Physiol Renal Physiol, July 1, 2007; 293(1): F139 - F147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Onozato, A. Tojo, N. Kobayashi, A. Goto, H. Matsuoka, and T. Fujita Dual blockade of aldosterone and angiotensin II additively suppresses TGF-{beta} and NADPH oxidase in the hypertensive kidney Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1314 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-P. Sun, M. Kohno, P. Guo, Y. Nagai, K. Miyata, Y.-Y. Fan, S. Kimura, H. Kiyomoto, K. Ohmori, D.-T. Li, et al. Involvements of Rho-Kinase and TGF-beta Pathways in Aldosterone-Induced Renal Injury J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2193 - 2201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nagase, S. Shibata, S. Yoshida, T. Nagase, T. Gotoda, and T. Fujita Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker Hypertension, June 1, 2006; 47(6): 1084 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kobayashi, K. Yoshida, S. Nakano, T. Ohno, T. Honda, Y. Tsubokou, and H. Matsuoka Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts Hypertension, April 1, 2006; 47(4): 671 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
|
|