GSE134804
Pan-ampk activation improves renal function in a rat model of progressive diabetic nephropathy
Chronic kidney disease (CKD) remains a tremendous and growing burden on the healthcare system and new therapies are needed to prevent or slow disease progression. 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 CKD. Merck has recently disclosed a pan-AMPK activator MK-8722 which was shown to have beneficial effects on metabolic parameters in preclinical models. In this study we investigate the effects of MK-8722 in a progressive model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We find that MK-8722 administration in a therapeutic paradigm is profoundly reno-protective. We provide evidence that the therapeutic effects may be mediated by modulation of renal mitochondrial quality control as well as by attenuating fibrotic and lipotoxic mechanisms in kidney cells. These data further validate the concept that targeting metabolic dysregulation in CKD could be a potential therapeutic approach. Overall design: Total RNA from kidney cortex and kidney medulla from rats treated with either vehicle, Enalapril, or MK-8722 (2 doses), for 28 weeks was sequenced (5 replicates per group).