Buléon Marie, Allard Julien, Jaafar Acil, Praddaude Françoise, Dickson Zara, Ranera Marie-Thérèse, Pecher Christiane, Girolami Jean-Pierre, Tack Ivan
Laboratoire de Physiologie, Faculté de Médecine Rangueil, Toulouse, France.
Am J Physiol Renal Physiol. 2008 May;294(5):F1249-56. doi: 10.1152/ajprenal.00501.2007. Epub 2008 Mar 26.
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.
使用血管紧张素转换酶抑制剂（ACEi）可延缓糖尿病肾病（DN）的发展。ACEi肾脏保护的机制并不明确。为了研究ACE抑制过程中缓激肽B2受体（B2R）激活的影响，II型糖尿病小鼠（C57BLKS db/db）接受了20周的治疗：1）单独使用ACEi（雷米普利），2）ACEi + HOE-140（一种特异性B2R拮抗剂），3）单独使用HOE-140，或4）不进行治疗。通过蛋白尿增加和肾小球硬化来定义的DN的发展在很大程度上被ACEi治疗所预防（蛋白尿：980±130 vs. 2160±330 mg/g肌酐；系膜面积：22.5±0.5 vs. 27.6±0.3%）。B2R阻断显著减弱了雷米普利的保护作用（蛋白尿：2790±680 mg/g肌酐；系膜面积：30.4±1.1%），而单独使用HOE-140则显著增加了蛋白尿。尽管有这些益处，但肾小球滤过率保持不变，这可能是由于该模型中糖尿病的降压作用与雷米普利的肾脏血流动力学作用相结合的结果。最后，ACEi的肾脏保护作用与肾小球中胰岛素样生长因子-1（IGF-1）和转化生长因子-β途径的过度表达显著降低有关，也与晚期糖基化终产物受体和通过4-羟基-2-壬烯醛（4-HNE）加合物评估的脂质过氧化显著降低有关。B2R的同时阻断部分恢复了IGF-1受体β和4-HNE复合物的肾小球过度表达。这些结果支持了B2R激活在介导ACEi对DN的肾脏保护中的关键作用，并为将B2R激活本身作为DN的一种新治疗方法的益处研究提供了理论依据。
