Recombinant advanced glycation end product receptor pharmacokinetics in normal and diabetic rats
Recombinant advanced glycation end product receptor pharmacokinetics in normal and diabetic rats
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DOI：
10.1124/mol.52.1.54
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发表时间：
1997-07-01
影响因子：
3.6
通讯作者：
Wautier, JL
中科院分区：
文献类型：
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作者：
Renard, C;Chappey, O;Wautier, JL
糖尿病患者的血管功能障碍与晚期糖基化终产物（AGE）的形成有关。我们以前表明，AGEs产生血管通透性的增加，并产生氧化应激后，结合到受体（AGEs）存在于内皮细胞。已从大鼠肺cDNA文库中克隆了一种属于免疫球蛋白超家族的35-kDa蛋白，并已在昆虫细胞中产生重组大鼠可溶性β-内酰胺酶（rR-β-内酰胺酶）。人和大鼠的cDNA序列高度保守。本文研究了正常和链脲佐菌素诱导的糖尿病大鼠静脉或腹腔注射（125）l-rR-γ-D的生物学效应和药代动力学。rR-β 1阻止白蛋白或菊粉通过牛主动脉内皮细胞单层的转移，恢复糖尿病大鼠中观察到的或正常大鼠中由糖尿病大鼠红细胞诱导的高通透性，并纠正静脉内或腹腔内给药后的活性氧中间体产生。静脉注射（125）l-rR-γ后，糖尿病大鼠的分布半衰期（0.15和4.01小时）比正常大鼠（0.02和0.21小时）长（p小于或等于0.01），消除半衰期也是如此（糖尿病，57.17小时;正常，26.02小时; p小于或等于0.01）。糖尿病大鼠的分布容积高于正常大鼠（分别为6.94和3.24升/kg; p = 0.049）。我们的研究表明，rR-CRP在体内具有生物活性，并且缓慢清除，这表明它可以被认为是一种潜在的治疗方法。
Vascular dysfunction in patients with diabetes mellitus is related to advanced glycation end product (AGE) formation. We previously showed that AGEs produce an increase in vascular permeability and generated an oxidant stress after binding to the receptor (RAGE) present on endothelium. RAGE, a 35-kDa protein that belongs to the immunoglobulin superfamily, has been cloned from a rat lung cDNA library, and recombinant rat soluble RAGE (rR-RAGE) has been produced in insect cells. The sequence of RAGE is highly conserved between human and rat. We studied the biological effect of rR-RAGE and pharmacokinetics of (125)l-rR-RAGE after intravenous or intraperitoneal administration in normal and streptozotocin-induced diabetic rats. rR-RAGE prevented albumin or inulin transfer through a bovine aortic endothelial cell monolayer, restored the hyperpermeability observed in diabetic rats or induced in normal rats by diabetic rat red blood cells, and corrected the reactive oxygen intermediate production after intravenous or intraperitoneal administration. After intravenous injection of (125)l-rR-RAGE, the distribution half-life was longer (p less than or equal to 0.01) in diabetic (0.15 and 4.01 hr) than in normal (0.02 and 0.21 hr) rats, as was the case for the elimination half-lives (diabetic, 57.17 hr; normal, 26.02 hr; p less than or equal to 0.01). Distribution volume was higher in diabetic than in normal rats (6.94 and 3.24 liter/kg, respectively; p = 0.049). Our study showed that rR-RAGE was biologically active in vivo and slowly cleared, which suggests it could be considered as a potential therapy.