CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

被引:54
作者
Arai, Kiyoshi [1 ]
Morikawa, Yuka [2 ]
Ubukata, Naoko [1 ]
Tsuruoka, Hiroyuki [3 ]
Homma, Tsuyoshi [1 ]
机构
[1] Daiichi Sankyo Co Ltd, End Organ Dis Labs, Tokyo, Japan
[2] Daiichi Sankyo Co Ltd, Rare Dis & LCM Labs, Tokyo, Japan
[3] Daiichi Sankyo Co Ltd, Venture Sci Labs, Tokyo, Japan
关键词
SALT-INDUCED HYPERTENSION; COLLAGEN GENE-EXPRESSION; BLOOD-PRESSURE; OXIDATIVE STRESS; RESISTANT HYPERTENSION; DIABETIC-NEPHROPATHY; KIDNEY REGENERATION; RHO-KINASE; ALDOSTERONE; DISEASE;
D O I
10.1124/jpet.116.234765
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[ 4( methylsulfonyl) phenyl]-5-[ 2-(trifluoromethyl) phenyl]-1H-pyrrole-3- carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury.
引用
收藏
页码:548 / 557
页数:10
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