Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model
Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model
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DOI：
10.1152/ajprenal.00501.2007
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发表时间：
2008-05-01
影响因子：
4.2
通讯作者：
Tack, Ivan
中科院分区：
文献类型：
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作者：
Buleon, Marie;Allard, Julien;Tack, Ivan
糖尿病肾病可以通过使用血管紧张素转换酶抑制剂(ACEI)来延缓。ACEI的肾脏保护机制并不是单一的。为了研究血管紧张素转换酶(ACE)抑制过程中缓激肽B-2受体(B2R)激活的影响，对II型糖尿病小鼠(C57BLKS db/db)进行了20wk的治疗：1)ACEI(雷米普利)，2)ACEI+HOE-140(B2R特异性拮抗剂)，3)HOE-140单独，或4)不处理。糖尿病肾病的发展以蛋白尿和肾小球硬化的增加为特征，ACEI治疗在很大程度上阻止了糖尿病肾病的发展(蛋白尿：980+/-130比2,160+/-330 mg/g肌酐；肾小球系膜面积：22.5+/-0.5比27.6+/-0.3%)。雷米普利的保护作用可被B2R阻滞剂显著减弱(蛋白尿：2,790+/-680 mg/g肌酐；系膜面积：30.4+/-1.1%)，而HOE-140单独使用则显著增加蛋白尿。尽管有这样的好处，肾小球滤过率保持不变，可能是因为在这个模型中糖尿病的降压作用和雷米普利的肾脏血流动力学作用的结合。最后，ACEI的肾脏保护作用与显著减少肾小球胰岛素样生长因子-1(IGF-1)和转化生长因子-β途径的过度表达有关，也与晚期糖基化终产物受体和4-羟基-2-壬烯醛(4-HNE)加合物评估的脂质过氧化有关。同时阻断B2R可部分恢复肾小球IGF-1受体β和4-HNE复合体的过度表达。这些结果支持B2R激活在ACEI对糖尿病肾病的肾脏保护中的关键作用，并为研究B2R激活本身作为一种新的治疗糖尿病肾病方法的益处提供了理论基础。
Diabetic nephropathy (DN) can be delayed by the use of angiotensin-converting enzyme inhibitors (ACEi). The mechanisms of ACEi renal protection are not univocal. To investigate the impact of bradykinin B-2 receptor (B2R) activation during ACE inhibition, type II diabetic mice (C57BLKS db/db) received for 20 wk: 1) ACEi (ramipril) alone, 2) ACEi + HOE-140 (a specific B2R antagonist), 3) HOE-140 alone, or 4) no treatment. The development of DN, defined by an increase in albuminuria and glomerulosclerosis, was largely prevented by ACEi treatment (albuminuria: 980 +/- 130 vs. 2,160 +/- 330 mg/g creatinine; mesangial area: 22.5 +/- 0.5 vs. 27.6 +/- 0.3%). The protective effect of ramipril was markedly attenuated by B2R blockade (albuminuria: 2,790 +/- 680 mg/g creatinine; mesangial area: 30.4 +/- 1.1%), whereas HOE-140 alone significantly increased albuminuria. Despite such benefits, glomerular filtration rate remained unchanged, probably because of the combination of the hypotensive effect of diabetes in this model and the renal hemodynamic action of ramipril. Finally, the renal protective effect of ACEi was associated with a marked decrease in glomerular overexpression of insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta pathways, but also in advanced glycation end product receptors and lipid peroxidation assessed by 4-hydroxy-2-nonenal (4-HNE) adducts. Concomitant blockade of B2R partly restored glomerular overexpression of IGF-1 receptor beta and 4-HNE complexes. These results support the critical role of B2R activation in the mediation of ACEi renal protection against DN and provide the rationale to examine the benefit of B2R activation by itself as a new therapeutic approach for DN.