Abstract
Chronic kidney disease (CKD) is prevalent in 9.1% of the global population and is a significant public health problem associated with increased morbidity and mortality. CKD is associated with highly prevalent physiological and metabolic disturbances such as hypertension, obesity, insulin resistance, cardiovascular disease, and aging, which are also risk factors for CKD pathogenesis and progression. Podocytes and proximal tubular cells of the kidney strongly express AMP-activated protein kinase (AMPK). AMPK plays essential roles in glucose and lipid metabolism, cell survival, growth, and inflammation. Thus, metabolic disease-induced renal diseases like obesity-related and diabetic chronic kidney disease demonstrate dysregulated AMPK in the kidney. Activating AMPK ameliorates the pathological and phenotypical features of both diseases. As a metabolic sensor, AMPK regulates active tubular transport and helps renal cells to survive low energy states. AMPK also exerts a key role in mitochondrial homeostasis and is known to regulate autophagy in mammalian cells. While the nutrient-sensing role of AMPK is critical in determining the fate of renal cells, the role of AMPK in kidney autophagy and mitochondrial quality control leading to pathology in metabolic disease-related CKD is not very clear and needs further investigation. This review highlights the crucial role of AMPK in renal cell dysfunction associated with metabolic diseases and aims to expand therapeutic strategies by understanding the molecular and cellular processes underlying CKD.
Highlights
Progressive decline in renal function leads to chronic kidney disease (CKD) and, end-stage renal disease (ESRD) requiring dialysis or transplantation
The downregulation of AMPK activity in obesity- and diabetes-induced CKD has been extensively reported in patients and in vivo and in vitro experimental models
Inhibition of AMPK activity in the kidney results from systemic metabolic dysregulation, signaling factors mediated by other dysfunctional tissues and organs, and intrarenal disturbances
Summary
Progressive decline in renal function leads to chronic kidney disease (CKD) and, end-stage renal disease (ESRD) requiring dialysis or transplantation. Systemic inflammation and dyslipidemia contribute to the initiation of oxidative stress and insulin resistance, leading to renal low-grade inflammation and fibrosis (Figure 1) [20] Both obesity- and diabetes-induced kidney disease are characterized by ectopic lipid depositions in the kidney and are associated with direct lipotoxicity in rodents and humans [21,22,23,24,25,26,27]. Studies have demonstrated an essential role of AMP-activated protein kinase (AMPK) dysregulation in obesity- and diabetes-associated kidney disease both in experimental and clinical models [28,29,30,31,32,33]. The skeletal muscle expresses the γ3 subunit, but this subunit is not expressed in the kidney
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