Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse.
Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse.
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DOI：
10.2337/db09-1766
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发表时间：
2010-08
期刊：
影响因子：
7.7
通讯作者：
Schmidt AM
中科院分区：
文献类型：
--
作者：
Reiniger N;Lau K;McCalla D;Eby B;Cheng B;Lu Y;Qu W;Quadri N;Ananthakrishnan R;Furmansky M;Rosario R;Song F;Rai V;Weinberg A;Friedman R;Ramasamy R;D'Agati V;Schmidt AM
先前的研究表明，晚期糖基化终产物受体(RAGE)的基因缺失或药物阻断可阻止与糖尿病肾病相关的肾小球早期结构变化。为了克服缺乏人类观察到的进行性肾小球硬化的小鼠模型的局限性，我们研究了RAGE在OVE26 1型小鼠糖尿病肾病中的作用，OVE26 1型小鼠是进行性肾小球硬化和肾功能下降的模型。我们用纯合子RAGE基因敲除(RKO)小鼠培育了OVE26小鼠，检测了与糖尿病肾病相关的结构变化，并使用菊粉清除研究和白蛋白：肌酐测量来评估肾功能。检测转化生长因子-β1和纤溶酶原激活物抑制物1基因产物的转录变化，以探讨OVE26小鼠系膜基质积聚的机制。OVE26小鼠RAGE基因缺失可减少肾肥大、系膜硬化、管型形成、肾小球基底膜增厚、足细胞减少和蛋白尿。在OVE26小鼠中观察到的肾小球滤过率显著降低29%的现象被RAGE基因的缺失完全阻止。OVE26肾皮质纤溶酶原激活物抑制物1、转化生长因子-β1、转化生长因子-β诱导和α-(IV)胶原基因转录水平显著降低。与OVE26肾皮质相比，OVE26 RKO的ROCK1活性显著降低。这些数据为RAGE在糖尿病肾病发病机制中的关键作用提供了令人信服的证据，并表明在长期糖尿病中针对RAGE的策略可能防止肾功能的丧失。
Previous studies showed that genetic deletion or pharmacological blockade of the receptor for advanced glycation end products (RAGE) prevents the early structural changes in the glomerulus associated with diabetic nephropathy. To overcome limitations of mouse models that lack the progressive glomerulosclerosis observed in humans, we studied the contribution of RAGE to diabetic nephropathy in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function. We bred OVE26 mice with homozygous RAGE knockout (RKO) mice and examined structural changes associated with diabetic nephropathy and used inulin clearance studies and albumin:creatinine measurements to assess renal function. Transcriptional changes in the Tgf-β1 and plasminogen activator inhibitor 1 gene products were measured to investigate mechanisms underlying accumulation of mesangial matrix in OVE26 mice. Deletion of RAGE in OVE26 mice reduced nephromegaly, mesangial sclerosis, cast formation, glomerular basement membrane thickening, podocyte effacement, and albuminuria. The significant 29% reduction in glomerular filtration rate observed in OVE26 mice was completely prevented by deletion of RAGE. Increased transcription of the genes for plasminogen activator inhibitor 1, Tgf-β1, Tgf-β–induced, and α1-(IV) collagen observed in OVE26 renal cortex was significantly reduced in OVE26 RKO kidney cortex. ROCK1 activity was significantly lower in OVE26 RKO compared with OVE26 kidney cortex. These data provide compelling evidence for critical roles for RAGE in the pathogenesis of diabetic nephropathy and suggest that strategies targeting RAGE in long-term diabetes may prevent loss of renal function.
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影响因子：
13.6
作者：
Tanji, N;Markowitz, GS;D'Agati, VD
通讯作者：
D'Agati, VD
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