Failure to sense energy depletion may be a novel therapeutic target in chronic kidney disease
Failure to sense energy depletion may be a novel therapeutic target in chronic kidney disease
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DOI：
10.1016/j.kint.2018.08.030
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发表时间：
2019-01-01
影响因子：
19.6
通讯作者：
Sohara, Eisei
中科院分区：
文献类型：
--
作者：
Kikuchi, Hiroaki;Sasaki, Emi;Sohara, Eisei
肾脏消耗大量的能量来调节容量状态和血压，并排出尿毒症毒素。确定导致慢性肾脏病（CKD）环境中能量不匹配的因素，并制定旨在改善这种不匹配的干预措施是关键的研究任务。尽管已知关键的细胞能量传感器5 '-腺苷一磷酸（AMP）激活的蛋白激酶（AMPK）在CKD中失活，但AMPK失调的机制尚不清楚。在CKD的小鼠模型中，代谢组学分析证实，尽管AMP：ATP比率较高，但肾脏中AMPK活化减少，表明AMPK不感知能量消耗。在CKD小鼠的心脏和骨骼肌中发现了类似的AMPK失活。几种尿毒症因子在体外和离体肾组织制备物中显示出抑制AMPK。特异性AMPK激活剂A-769662绕过了AMP传感机制，改善了CKD小鼠肾脏的纤维化并改善了能量状态，而AMP类似物则不然。我们进一步证明，低蛋白饮食激活AMPK独立于AMP传感机制，导致能量代谢和肾脏纤维化的改善。这些结果表明，未能感知AMP是导致能量消耗和CKD进展的恶性循环的关键机制，直接激活AMPK可能是CKD的一种新的治疗方法。
The kidneys consume a large amount of energy to regulate volume status and blood pressure and to excrete uremic toxins. The identification of factors that cause energy mismatch in the setting of chronic kidney disease (CKD) and the development of interventions aimed at improving this mismatch are key research imperatives. Although the critical cellular energy sensor 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is known to be inactivated in CKD, the mechanism of AMPK dysregulation is unknown. In a mouse model of CKD, metabolome analysis confirmed a decrease in AMPK activation in the kidneys despite a high AMP: ATP ratio, suggesting that AMPK did not sense energy depletion. Similar AMPK inactivation was found in heart and skeletal muscle in CKD mice. Several uremic factors were shown to inactivate AMPK in vitro and in ex vivo preparations of kidney tissue. The specific AMPK activator A-769662, which bypasses the AMP sensing mechanism, ameliorated fibrosis and improved energy status in the kidneys of CKD mice, whereas an AMP analog did not. We further demonstrated that a low-protein diet activated AMPK independent of the AMP sensing mechanism, leading to improvement in energy metabolism and kidney fibrosis. These results suggest that a failure to sense AMP is the key mechanism underlying the vicious cycle of energy depletion and CKD progression and direct AMPK activation may be a novel therapeutic approach in CKD.