A novel sartan derivative with very low angiotensin II type 1 receptor affinity protects the kidney in type 2 diabetic rats

被引：25

作者：

Izuhara, Yuko ^{[1
]}

Sada, Toshio ^{[2
]}

Yanagisawa, Hiroaki ^{[2
]}

Koike, Hiroyuki ^{[2
]}

Ohtomo, Shuichi ^{[1
]}

Dan, Takashi ^{[1
]}

Ito, Sadayoshi ^{[3
]}

Nangaku, Masaomi ^{[4
]}

de Strihou, Charles van Ypersele ^{[5
]}

Miyata, Toshio ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Med, Ctr Translat & Adv Res, Aoba Ku, Sendai, Miyagi 9808575, Japan

[2] Daiichi Sankyo Co Ltd, R & D Div, Tokyo, Japan

[3] Tohoku Univ, Grad Sch Med, Div Nephrol & Hypertens, Sendai, Miyagi 9808575, Japan

[4] Univ Tokyo, Sch Med, Div Nephrol & Endocrinol, Tokyo 113, Japan

[5] Univ Catholique Louvain, Serv Nephrol, B-1200 Brussels, Belgium

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2008年 / 28卷 / 10期

关键词：

blood pressure; renoprotection; advanced glycation end products; oxidative stress; type; 2; diabetes;

D O I：

10.1161/ATVBAHA.108.172841

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background - Antihypertensive angiotensin II receptor blockers (ARBs) protect the kidney, at least in part, independently of blood pressure lowering. Still, the extent to which blood pressure lowering is related to renoprotection remains unclear. Methods and Results - 139 newly synthesized ARB-derivatives were assayed for inhibition of advanced glycation (AGEs). The 9 most powerful compounds were then tested for transition metal chelation, angiotensin II type 1 receptor (AT1R) affinity, and pharmacokinetic parameters. R-147176 was eventually selected as it strongly inhibits advanced glycation but is 6700 times less effective than olmesartan in AT1R binding. It is orally bioavailable and toxicologically safe. Despite a minimal blood pressure lowering effect, it provides significant renoprotection in 3 experimental rat models with renal injury, ie, obese, hypertensive, type 2 diabetic rats (SHR/NDmcr-cp), normotensive type 2 diabetic rats (Zucker diabetic fatty), and remnant kidney rats. Conclusion - R-147176 retains renal protective properties despite a minimal blood pressure -lowering effect. Clearly, the renal benefits of ARBs do not necessarily depend on blood pressure lowering and AT1R affinity, but rather on the inhibition of AGEs and oxidative stress inherent to their chemical structure. R-147176 opens new avenues in the treatment of cardiovascular and kidney diseases.

引用

页码：1767 / 1773

页数：7

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