Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey
Department of Cardiometabolic Diseases (X.Z., R.H., Y.Z., F.L., S.C.S., Y.K., S.P., D.E.K., M.H.), Genetics and Pharmacogenomics (E.S.M.), and Medicinal Chemistry (I.K.S.), Merck & Co., Inc., Kenilworth, New Jersey.
J Pharmacol Exp Ther. 2019 Oct;371(1):45-55. doi: 10.1124/jpet.119.258244. Epub 2019 Jul 12.
Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate-activated protein kinase (AMPK) may be an effective therapeutic target for chronic kidney disease (CKD). We have recently disclosed a pan-AMPK activator, MK-8722, that was shown to have beneficial effects in preclinical models. In this study we investigated the effects of MK-8722 in a progressive rat model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We found that MK-8722 administration in a therapeutic paradigm is profoundly renoprotective, as demonstrated by a reduction in proteinuria (63% decrease in MK-8722 10 mg/kg per day compared with vehicle group) and a significant improvement in glomerular filtration rate (779 and 430 l/min per gram kidney weight in MK-8722 10 mg/kg per day and vehicle group, respectively), as well as improvements in kidney fibrosis. We provide evidence that the therapeutic effects of MK-8722 may be mediated by modulation of renal mitochondrial quality control as well by attenuating fibrotic and lipotoxic mechanisms in kidney cells. MK-8722 (10 mg/kg per day compared with vehicle group) achieved modest blood pressure reduction (10 mmHg lower for mean blood pressure) and significant metabolic improvements (decreased plasma glucose, triglyceride, and body weight) that could contribute to renoprotection. These data further validate the concept that targeting metabolic dysregulation in CKD could be a potential therapeutic approach. SIGNIFICANCE STATEMENT: We demonstrate in the present study that the pharmacological activation of AMPK using a small-molecule agent provided renoprotection and improved systemic and cellular metabolism. We further indicate that modulation of renal mitochondrial quality control probably contributed to renoprotection and was distinct from the effects of enalapril. Our findings suggest that improving renal mitochondrial biogenesis and function and attenuating fibrosis and lipotoxicity by targeting key metabolic nodes could be a potential therapeutic approach in management of CKD that could complement the current standard of care.
代谢失调和线粒体功能障碍是跨物种急性和慢性组织损伤的重要特征，人类遗传学和临床前数据表明，主代谢调节剂 5'-腺苷单磷酸激活蛋白激酶（AMPK）可能是慢性肾脏病（CKD）的有效治疗靶点。我们最近公布了一种泛 AMPK 激活剂 MK-8722，在临床前模型中显示出有益的效果。在这项研究中，我们研究了 MK-8722 在糖尿病肾病进行性大鼠模型中的作用，以确定 AMPK 的激活是否具有治疗益处。我们发现，MK-8722 在治疗方案中的给药具有显著的肾脏保护作用，表现在蛋白尿减少（MK-8722 10mg/kg/天组与对照组相比减少 63%）和肾小球滤过率显著改善（MK-8722 10mg/kg/天组和对照组分别为 779 和 430l/min/克肾重），以及肾脏纤维化的改善。我们提供的证据表明，MK-8722 的治疗效果可能是通过调节肾脏线粒体质量控制以及减轻肾脏细胞中的纤维化和脂肪毒性机制来介导的。与对照组相比，MK-8722（10mg/kg/天）实现了适度的血压降低（平均血压降低 10mmHg）和显著的代谢改善（降低血浆葡萄糖、甘油三酯和体重），这可能有助于肾脏保护。这些数据进一步验证了这样一种概念，即在 CKD 中靶向代谢失调可能是一种潜在的治疗方法。
在本研究中，我们证明使用小分子药物激活 AMPK 可提供肾脏保护作用，并改善全身和细胞代谢。我们进一步表明，调节肾脏线粒体质量控制可能有助于肾脏保护，并且与依那普利的作用不同。我们的研究结果表明，通过靶向关键代谢节点改善肾脏线粒体生物发生和功能，并减轻纤维化和脂肪毒性，可能是管理 CKD 的一种潜在治疗方法，可补充当前的标准治疗方法。
