Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease
Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease
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DOI：
10.1152/ajprenal.00293.2013
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发表时间：
2013-09-01
影响因子：
4.2
通讯作者：
Deng, Aihua
中科院分区：
文献类型：
--
作者：
Satriano, Joseph;Sharma, Kumar;Deng, Aihua
大鼠肾消融和梗死（A/I）模型的次全或5/6肾切除术是最常用的非糖尿病慢性肾脏疾病（CKD）的研究模型。A/I肾在1周时表现出肾功能降低（通过肾小球滤过率测定）和代谢效率降低（通过每次钠转运的耗氧量（Q（O2）/T-Na）测定）。由于肾脏保护性AMPK活性受代谢变化和细胞应激的影响，我们在该模型系统中评估了AMPK活性。我们发现，这些早期的病理生理变化伴随着一个矛盾的AMPK活性下降。随着时间的推移，这些肾脏参数逐渐恶化，A/I后4周观察到广泛的肾脏结构、功能、代谢和纤维化变化。我们发现，无论是二甲双胍或5-氨基咪唑-4-甲酰胺核苷酸诱导AMPK活性增加AMPK活性在这个模型中，也纠正肾脏代谢效率低下，改善肾功能，改善肾纤维化和结构改变。我们的结论是，AMPK活性降低，在非糖尿病CKD的肾大部切除模型，AMPK的调节改变是一致的疾病参数的进展，AMPK活性的恢复可以抑制功能的进行性丧失，这种模式的特点。我们认为AMPK活性的诱导可能被证明是治疗非糖尿病CKD的有效治疗靶点。
The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (Q(O2)/T-Na). As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system. We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model. We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.