Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function.
Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function.
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DOI：
10.2337/db10-0552
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发表时间：
2010-12
期刊：
影响因子：
7.7
通讯作者：
Wilkinson-Berka JL
中科院分区：
文献类型：
--
作者：
Miller AG;Tan G;Binger KJ;Pickering RJ;Thomas MC;Nagaraj RH;Cooper ME;Wilkinson-Berka JL
晚期糖基化终产物（AGEs）和肾素血管紧张素系统（RAS）都与糖尿病视网膜病变的发展有关。这些途径如何相互作用以促进视网膜血管病变尚不完全清楚。Glyoxalase-I （gloi）是一种对AGEs解毒和视网膜血管细胞存活至关重要的酶。我们假设，在视网膜中，血管紧张素II （Ang II）下调gloi，从而导致甲基乙二醛- age形成的增加。血管紧张素1型受体阻滞剂坎地沙坦可以纠正这种不平衡，防止视网膜血管病变。将培养的牛视网膜内皮细胞（BREC）和牛视网膜周细胞（BRP）与Ang II （100 nmol/l）或Ang II+坎地沙坦（1 μmol/l）孵育。将RAS过表达的转基因Ren-2大鼠随机分为非糖尿病组、糖尿病组和糖尿病+坎地沙坦组（5 mg/kg/天），研究时间超过20周。与糖尿病大鼠进行比较。在BREC和BRP中，Ang II诱导细胞凋亡，降低gloi活性和mRNA，同时增加一氧化氮（NO•），后者是已知的BRP中gloi的负调节因子。在BREC和BRP中，坎地沙坦恢复gloi并降低NO•。在体内也发生了类似的事件，糖尿病Ren-2大鼠的RAS升高，而糖尿病Sprague-Dawley大鼠的RAS升高，降低了视网膜gloi。在糖尿病Ren-2大鼠中，坎地沙坦减少视网膜脱细胞毛细血管，炎症，诱导型一氧化氮合酶和NO•，并恢复gloi。我们已经确定了坎地沙坦通过恢复gloi改善糖尿病视网膜病变的新机制。
Advanced glycation end products (AGEs) and the renin-angiotensin system (RAS) are both implicated in the development of diabetic retinopathy. How these pathways interact to promote retinal vasculopathy is not fully understood. Glyoxalase-I (GLO-I) is an enzyme critical for the detoxification of AGEs and retinal vascular cell survival. We hypothesized that, in retina, angiotensin II (Ang II) downregulates GLO-I, which leads to an increase in methylglyoxal-AGE formation. The angiotensin type 1 receptor blocker, candesartan, rectifies this imbalance and protects against retinal vasculopathy. Cultured bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRP) were incubated with Ang II (100 nmol/l) or Ang II+candesartan (1 μmol/l). Transgenic Ren-2 rats that overexpress the RAS were randomized to be nondiabetic, diabetic, or diabetic+candesartan (5 mg/kg/day) and studied over 20 weeks. Comparisons were made with diabetic Sprague-Dawley rats. In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO•), the latter being a known negative regulator of GLO-I in BRP. In BREC and BRP, candesartan restored GLO-I and reduced NO•. Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO-I. In diabetic Ren-2 rats, candesartan reduced retinal acellular capillaries, inflammation, and inducible nitric oxide synthase and NO•, and restored GLO-I. We have identified a novel mechanism by which candesartan improves diabetic retinopathy through the restoration of GLO-I.