Novel AMP-activated protein kinase activators and their potential for mitigating renal injury and fibrosis

Disordered energy regulation within the kidney represents an important therapeutic target to reduce the severity of acute kidney injury and subsequent fibrosis. AMP-activated protein kinase (AMPK) is stimulated in situations of cellular energy deprivation to act as a key regulator of cellular and systemic energy metabolism. AMPK activation has been shown to be protective against renal injury and fibrosis in numerous experimental studies using metformin and aminoimidazole-4-carboxamide ribonucleotide. However, studies with these traditional AMPK activators are limited by these agents being indirect activators of AMPK, with unwanted off-target effects that may limit their use. Novel AMPK activators represent a promising new therapy in kidney protection, as well as in a range of other chronic diseases. AMPK phosphorylates multiple targets to regulate numerous pathways, thereby enabling multiple mechanisms to reduce kidney injury. This review outlines important mechanisms of renal injury and fibrosis as well as the current landscape of novel AMPK activators. It outlines experimental evidence for mechanisms of novel AMPK activators and how these relate to injury and fibrosis within the kidney. Finally, it discusses the potential of these agents, as well as current challenges in their development. SIGNIFICANCE STATEMENT: Multiple studies have identified dysregulated energy metabolism as a treatment target for kidney disease, revealing novel AMP-activated protein kinase (AMPK) activators as a promising new therapy to address this opportunity for protection against kidney injury and fibrosis. Despite this promise, novel AMPK activators are yet to find a clinical role for kidney disease or other conditions. Barriers to be considered in future studies include concerns about cardiac hypertrophy and oncogenesis as well as elucidation of precise pharmacokinetic properties. Nonetheless, the large volume of beneficial preclinical data for kidney health provides motivation for future studies to address these needs.