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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/F802    most recent 00197.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Du, J. Articles by Nakano, D. PubMed PubMed Citation Articles by Du, J. Articles by Nakano, D.

Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats

Departments of ¹Pharmacology and ²Cardiorenal and Cerebrovascular Medicine, Kagawa University Medical School, Kagawa, Japan; and ³Department of Urology, First Affiliated Hospital of China Medical University, Shenyang, China

Submitted 8 April 2009 ; accepted in final form 12 June 2009

We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle (n = 12), eplerenone (50 mg·kg^–1·day^–1, po, n = 12), amlodipine (3 mg·kg^–1·day^–1, po, n = 12), or eplerenone plus amlodipine (n = 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects.

interstitial fibrosis; hypoxia; salt-sensitive hypertension