Akt1-Mediated Fast/Glycolytic Skeletal Muscle Growth Attenuates Renal Damage in Experimental Kidney Disease
Akt1-Mediated Fast/Glycolytic Skeletal Muscle Growth Attenuates Renal Damage in Experimental Kidney Disease
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DOI：
10.1681/asn.2013091025
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发表时间：
2014-12-01
影响因子：
13.6
通讯作者：
Ogawa, Hisao
中科院分区：
文献类型：
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作者：
Hanatani, Shinsuke;Izumiya, Yasuhiro;Ogawa, Hisao
肾脏疾病患者经常会出现肌肉萎缩，在这些患者中，肌肉力量不足与预后不良有关。然而，人们对骨骼肌生长本身对肾脏疾病的影响知之甚少。在这项研究中，我们利用骨骼肌特异的、可诱导的Akt1转基因(Akt1 TG)小鼠模型，促进不依赖运动的功能性骨骼肌的生长，以探讨肌肉生长对肾脏疾病的影响。Akt1激活骨骼肌后7d，用单侧输尿管梗阻(UUO)诱导Akt1转基因小鼠和野生型(WT)对照组小鼠肾损伤。骨骼肌萎缩诱导基因AUGIN-1在WT小鼠UUO后7d表达上调，而在Akt1Tg小鼠无表达。与WT小鼠相比，Akt1Tg小鼠UUO诱导的肾间质纤维化、肾小管损伤、细胞凋亡以及炎症、纤维化相关和黏附分子基因的表达增加显著减少。肌源性Akt1激活减轻肾脏损伤的同时，肾脏eNOS的活化磷酸化增加。用一氧化氮合酶抑制剂L-NAME治疗后，骨骼肌Akt激活对梗阻性肾脏疾病的保护作用消失。总而言之，Akt1介导的肌肉生长减少了梗阻性肾脏疾病模型中的肾脏损害。这种改善似乎是由肾脏中eNOS信号的增加所介导的。我们的数据支持这样的概念，即肾脏疾病期间肌肉质量的丧失会导致肾功能衰竭，而保持肌肉质量可能会改善临床结果。
Muscle wasting is frequently observed in patients with kidney disease, and low muscle strength is associated with poor outcomes in these patients. However, little is known about the effects of skeletal muscle growth per se on kidney diseases. In this study, we utilized a skeletal muscle-specific, inducible Akt1 transgenic (Akt1 TG) mouse model that promotes the growth of functional skeletal muscle independent of exercise to investigate the effects of muscle growth on kidney diseases. Seven days after Akt1 activation in skeletal muscle, renal injury was induced by unilateral ureteral obstruction (UUO) in Akt1 TG and wild-type (WT) control mice. The expression of atrogin-1, an atrophy-inducing gene in skeletal muscle, was upregulated 7 days after UUO in WT mice but not in Akt1 TG mice. UUO-induced renal interstitial fibrosis, tubular injury, apoptosis, and increased expression of inflammatory, fibrosis-related, and adhesion molecule genes were significantly diminished in Akt1 TG mice compared with WT mice. An increase in the activating phosphorylation of eNOS in the kidney accompanied the attenuation of renal damage by myogenic Akt1 activation. Treatment with the NOS inhibitor L-NAME abolished the protective effect of skeletal muscle Akt activation on obstructive kidney disease. In conclusion, Akt1-mediated muscle growth reduces renal damage in a model of obstructive kidney disease. This improvement appears to be mediated by an increase in eNOS signaling in the kidney. Our data support the concept that loss of muscle mass during kidney disease can contribute to renal failure, and maintaining muscle mass may improve clinical outcome.