Nutrients such as glucose, amino acids and lipids are fundamental sources for the maintenance of essential cellular processes and homeostasis in all organisms. The nutrient-sensing kinases mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are expressed in many cell types and have key roles in the control of cell growth, proliferation, differentiation, metabolism and survival, ultimately contributing to the physiological development and functions of various organs, including the kidney. Dysregulation of these kinases leads to many human health problems, including cancer, neurodegenerative diseases, metabolic disorders and kidney diseases. In the kidney, physiological levels of mTOR and AMPK activity are required to support kidney cell growth and differentiation and to maintain kidney cell integrity and normal nephron function, including transport of electrolytes, water and glucose. mTOR forms two functional multi-protein kinase complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Hyperactivation of mTORC1 leads to podocyte and tubular cell dysfunction and vulnerability to injury, thereby contributing to the development of chronic kidney diseases, including diabetic kidney disease, obesity-related kidney disease and polycystic kidney disease. Emerging evidence suggests that targeting mTOR and/or AMPK could be an effective therapeutic approach to controlling or preventing these diseases.
mTORC1 and AMPK function as key nutrient-sensing kinases and govern anabolic and catabolic cellular processes.
Balanced cellular mTORC1 and AMPK activity are critical for maintaining the physiological functions of kidney cells including podocytes and renal tubular cells.
Dysregulation of mTORC1 and AMPK signalling contributes to the pathogenesis of kidney diseases that are associated with metabolic, proliferative and ischaemic disorders.
Restoration of balanced mTORC1 and AMPK activity is a critical therapeutic approach for the prevention of kidney diseases and may be a mechanism by which metformin and SGLT2 inhibitors have kidney-protective effects.
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The authors’ work is supported by National Institute of Health (NIH) RO1 grants (DK124709 and GM145631) to K. I.
The authors declare no competing interests.
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Nature Reviews Nephrology thanks Lu Cai, who co-reviewed with Madhavi Rane, Anne-Emilie Declèves, Sandra Galic and the other, anonymous, reviewer for their contribution to the peer review of this work.
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Animals that subsist totally or primarily on fruit.
- Michaelis constant (Km)
The substrate concentration at which half of the maximum reaction rate is achieved.
Selective removal of damaged mitochondria by the autophagic machinery.
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Huynh, C., Ryu, J., Lee, J. et al. Nutrient-sensing mTORC1 and AMPK pathways in chronic kidney diseases. Nat Rev Nephrol 19, 102–122 (2023). https://doi.org/10.1038/s41581-022-00648-y