RAGE control of diabetic nephropathy in a mouse model -: Effects of RAGE gene disruption and administration of low-molecular weight heparin
RAGE control of diabetic nephropathy in a mouse model -: Effects of RAGE gene disruption and administration of low-molecular weight heparin
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DOI：
10.2337/db06-0221
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发表时间：
2006-09-01
期刊：
影响因子：
7.7
通讯作者：
Yamamoto, Hiroshi
中科院分区：
文献类型：
--
作者：
Myint, Khin-Mar;Yamamoto, Yasuhiko;Yamamoto, Hiroshi
肾病是长期糖尿病患者最终接受肾透析或肾移植的主要微血管并发症。为了预防这种疾病的发展并改善晚期肾损伤，需要针对关键分子靶点的有效治疗。在这项研究中，我们研究了是否抑制晚期糖基化终末产物（AGEs）受体可以减轻糖尿病肾脏的变化。在此，我们发现，与野生型糖尿病小鼠相比，在糖尿病肾病小鼠模型中，β-淀粉样蛋白基因的失活导致肾脏变化的显著抑制，包括肾脏增大、肾小球细胞数量增加、系膜扩张、晚期肾小球硬化、白蛋白尿增加和血清肌酐增加。肾损伤程度与PAGE基因剂量成正比。此外，我们表明，低分子量肝素（LMWH）可以结合在一个平均平衡解离常数（k（d））值类似于17 nmol/l的，并作为一种拮抗剂，以抑制。LMWH治疗小鼠显著预防蛋白尿，并以剂量依赖性方式增加肾小球细胞数量、系膜扩张和肾小球硬化;它还显著改善晚期糖尿病肾病的指标。这项研究提供了深入了解的病理作用，在早期和晚期糖尿病肾病，并表明，β受体拮抗剂将是一个有用的补救措施，在治疗糖尿病肾病。
Nephropathy is a major microvascular complication in long-standing diabetic patients who eventually undergo renal dialysis or transplantation. To prevent development of this disease and to improve advanced kidney injury, effective therapies directed toward the key molecular target are required. In this study, we examined whether inhibition of the receptor for advanced glycation end products (RAGE) could attenuate changes in the diabetic kidney. Here, we show that inactivation of the RAGE gene in a mouse model of diabetic nephropathy results in significant suppression of kidney changes, including kidney enlargement, increased glomerular cell number, mesangial expansion, advanced glomerulosclerosis, increased albuminuria, and increased serum creatinine compared with wild-type diabetic mice. The degree of kidney injury was proportional to PAGE gene dosage. Furthermore, we show that low-molecular weight heparin (LMWH) can bind RAGE at a mean equilibrium dissociation constant (k(d)) value of similar to 17 nmol/l and act as an antagonist to RAGE. LMWH treatment of mice significantly prevented albuminuria and increased glomerular cell number, mesangial expansion, and glomerulosclerosis in a dose-dependent manner; it also significantly improved the indexes of advanced-stage diabetic nephropathy. This study provides insight into the pathological role of RAGE in both early and advanced-phase diabetic nephropathy and suggests that RAGE antagonists will be a useful remedy in the treatment of diabetic nephropathy.