Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Nutrient-sensing mTORC1 and AMPK pathways in chronic kidney diseases

Nature Reviews Nephrology volume 19, pages 102–122 (2023)Cite this article

Subjects

Abstract

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.

Key points

  • 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The mTORC1 and mTORC2 complexes.
Fig. 2: The amino acid and growth factor-sensing machinery for mTORC1 activation.
Fig. 3: Glucose and lipid-sensing machinery for mTORC1 activation.
Fig. 4: AMPK activation and regulation.
Fig. 5: Glucose sensing regulates lysosomal localization of AMPK and mTORC1.
Fig. 6: AMPK effectors and downstream pathways.
Fig. 7: Podocyte and proximal tubule homeostasis depend on a balance between mTORC1 and AMPK activity.

Similar content being viewed by others

References

  1. Gonzalez, A., Hall, M. N., Lin, S. C. & Hardie, D. G. AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth control. Cell Metab. 31, 472–492 (2020).

    Article  CAS  Google Scholar 

  2. Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).

    Article  CAS  Google Scholar 

  3. Trefts, E. & Shaw, R. J. AMPK: restoring metabolic homeostasis over space and time. Mol. Cell 81, 3677–3690 (2021).

    Article  CAS  Google Scholar 

  4. Dagon, Y. et al. p70S6 Kinase phosphorylates AMPK on serine 491 to mediate Leptin’s effect on food intake. Cell Metab. 16, 104–112 (2012).

    Article  CAS  Google Scholar 

  5. Madeo, F., Carmona-Gutierrez, D., Hofer, S. J. & Kroemer, G. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential. Cell Metab. 29, 592–610 (2019).

    Article  CAS  Google Scholar 

  6. Carling, D. AMPK signalling in health and disease. Curr. Opin. Cell Biol. 45, 31–37 (2017).

    Article  CAS  Google Scholar 

  7. Cornu, M., Albert, V. & Hall, M. N. mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev. 23, 53–62 (2013).

    Article  CAS  Google Scholar 

  8. Puelles, V. G. et al. mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. JCI Insight https://doi.org/10.1172/jci.insight.99271 (2019).

    Article  Google Scholar 

  9. Zschiedrich, S. et al. Targeting mTOR signaling can prevent the progression of FSGS. J. Am. Soc. Nephrol. 28, 2144–2157 (2017).

    Article  CAS  Google Scholar 

  10. Pastor-Soler, N. M. et al. Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model. Am. J. Physiol. Renal Physiol. 322, F27–F41 (2022).

    Article  CAS  Google Scholar 

  11. Tao, Y., Kim, J., Schrier, R. W. & Edelstein, C. L. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J. Am. Soc. Nephrol. 16, 46–51 (2005).

    Article  CAS  Google Scholar 

  12. Perrone, R. D. et al.Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD. Kidney Int. 100, 684–696 (2021).

    Article  CAS  Google Scholar 

  13. Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28, 721–726 (1975).

    Article  CAS  Google Scholar 

  14. Heitman, J., Movva, N. R. & Hall, M. N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905–909 (1991).

    Article  CAS  Google Scholar 

  15. Kunz, J. et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585–596 (1993).

    Article  CAS  Google Scholar 

  16. Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

    Article  CAS  Google Scholar 

  17. Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).

    Article  CAS  Google Scholar 

  18. Chiu, M. I., Katz, H. & Berlin, V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc. Natl Acad. Sci. USA 91, 12574–12578 (1994).

    Article  CAS  Google Scholar 

  19. Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002).

    Article  CAS  Google Scholar 

  20. Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122–1128 (2004).

    Article  CAS  Google Scholar 

  21. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    Article  CAS  Google Scholar 

  22. Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

    Article  CAS  Google Scholar 

  23. Gaubitz, C. et al. Molecular basis of the rapamycin insensitivity of target of rapamycin complex 2. Mol. Cell 58, 977–988 (2015).

    Article  CAS  Google Scholar 

  24. Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

    Article  CAS  Google Scholar 

  25. Yip, C. K., Murata, K., Walz, T., Sabatini, D. M. & Kang, S. A. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 38, 768–774 (2010).

    Article  CAS  Google Scholar 

  26. Settembre, C. et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095–1108 (2012).

    Article  CAS  Google Scholar 

  27. Canaud, G. et al. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat. Med. 19, 1288–1296 (2013).

    Article  CAS  Google Scholar 

  28. Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).

    Article  CAS  Google Scholar 

  29. Senoo, H. et al. KARATE: PKA-induced KRAS4B-RHOA-mTORC2 supercomplex phosphorylates AKT in insulin signaling and glucose homeostasis. Mol. Cell 81, 4622–4634 e4628 (2021).

    Article  CAS  Google Scholar 

  30. Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol. Cell 10, 151–162 (2002).

    Article  CAS  Google Scholar 

  31. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 (2002).

    Article  CAS  Google Scholar 

  32. Meng, D. et al. Glutamine and asparagine activate mTORC1 independently of Rag GTPases. J. Biol. Chem. 295, 2890–2899 (2020).

    Article  CAS  Google Scholar 

  33. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998).

    Article  CAS  Google Scholar 

  34. Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43–48 (2016).

    Article  CAS  Google Scholar 

  35. Chen, J. et al. SAR1B senses leucine levels to regulate mTORC1 signalling. Nature 596, 281–284 (2021).

    Article  CAS  Google Scholar 

  36. Chantranupong, L. et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164 (2016).

    Article  CAS  Google Scholar 

  37. Wang, S. et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188–194 (2015).

    Article  CAS  Google Scholar 

  38. Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).

    Article  CAS  Google Scholar 

  39. proteinatlas. SAR1B — The Human Protein Atlas https://www.proteinatlas.org/search/SAR1B (2021).

  40. Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).

    Article  CAS  Google Scholar 

  41. Shen, K. & Sabatini, D. M. Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms. Proc. Natl Acad. Sci. USA 115, 9545–9550 (2018).

    Article  CAS  Google Scholar 

  42. Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).

    Article  CAS  Google Scholar 

  43. Fromm, S. A., Lawrence, R. E. & Hurley, J. H. Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9. Nat. Struct. Mol. Biol. 27, 1017–1023 (2020).

    Article  CAS  Google Scholar 

  44. Napolitano, G. et al. A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dube syndrome. Nature 585, 597–602 (2020).

    Article  CAS  Google Scholar 

  45. Dibble, C. C. et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47, 535–546 (2012).

    Article  CAS  Google Scholar 

  46. Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes. Dev. 17, 1829–1834 (2003).

    Article  CAS  Google Scholar 

  47. Menon, S. et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771–785 (2014).

    Article  CAS  Google Scholar 

  48. Demetriades, C., Doumpas, N. & Teleman, A. A. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell 156, 786–799 (2014).

    Article  CAS  Google Scholar 

  49. Yao, Y. et al. Amino acids enhance polyubiquitination of Rheb and its binding to mTORC1 by blocking lysosomal ATXN3 deubiquitinase activity. Mol. Cell 80, 437–451 e436 (2020).

    Article  CAS  Google Scholar 

  50. Liu, P. et al. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov. 5, 1194–1209 (2015).

    Article  CAS  Google Scholar 

  51. Krishna, S. et al. PIKfyve regulates vacuole maturation and nutrient recovery following engulfment. Dev. Cell 38, 536–547 (2016).

    Article  CAS  Google Scholar 

  52. Hasegawa, J. et al. PP2A-dependent TFEB activation is blocked by PIKfyve-induced mTORC1 activity. Mol. Biol. Cell 33, ar26 (2022).

    Article  CAS  Google Scholar 

  53. Fitzian, K. et al. TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation. Mol. Cell 81, 2705–2721 e2708 (2021).

    Article  CAS  Google Scholar 

  54. Castellano, B. M. et al. Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science 355, 1306–1311 (2017).

    Article  CAS  Google Scholar 

  55. Lim, C. Y. et al. ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C. Nat. Cell Biol. 21, 1206–1218 (2019).

    Article  CAS  Google Scholar 

  56. Shin, H. R. et al. Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1. Science 377, 1290–1298 (2022).

    Article  CAS  Google Scholar 

  57. Davis, O. B. et al. NPC1-mTORC1 signaling couples cholesterol sensing to organelle homeostasis and is a targetable pathway in Niemann-Pick type C. Dev. Cell 56, 260–276 e267 (2021).

    Article  CAS  Google Scholar 

  58. Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A. & Chen, J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294, 1942–1945 (2001).

    Article  CAS  Google Scholar 

  59. Kooijman, E. E. & Burger, K. N. Biophysics and function of phosphatidic acid: a molecular perspective. Biochim. Biophys. Acta 1791, 881–888 (2009).

    Article  CAS  Google Scholar 

  60. Foster, D. A. Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells. Biochim. Biophys. Acta 1791, 949–955 (2009).

    Article  CAS  Google Scholar 

  61. Huang, C., Bruggeman, L. A., Hydo, L. M. & Miller, R. T. Shear stress induces cell apoptosis via a c-Src-phospholipase D-mTOR signaling pathway in cultured podocytes. Exp. Cell Res. 318, 1075–1085 (2012).

    Article  CAS  Google Scholar 

  62. Frias, M. A. et al. Phosphatidic acid drives mTORC1 lysosomal translocation in the absence of amino acids. J. Biol. Chem. 295, 263–274 (2020).

    Article  CAS  Google Scholar 

  63. Orozco, J. M. et al. Dihydroxyacetone phosphate signals glucose availability to mTORC1. Nat. Metab. 2, 893–901 (2020).

    Article  CAS  Google Scholar 

  64. Inoki, K., Zhu, T. & Guan, K.-L. TSC2 Mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    Article  CAS  Google Scholar 

  65. Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

    Article  CAS  Google Scholar 

  66. Tappy, L. & Rosset, R. Health outcomes of a high fructose intake: the importance of physical activity. J. Physiol. 597, 3561–3571 (2019).

    Article  CAS  Google Scholar 

  67. Nakagawa, T. et al. Fructose production and metabolism in the kidney. J. Am. Soc. Nephrol. 31, 898–906 (2020).

    Article  CAS  Google Scholar 

  68. Battaglioni, S., Benjamin, D., Walchli, M., Maier, T. & Hall, M. N. mTOR substrate phosphorylation in growth control. Cell 185, 1814–1836 (2022).

    Article  CAS  Google Scholar 

  69. Puente, C., Hendrickson, R. C. & Jiang, X. Nutrient-regulated phosphorylation of ATG13 inhibits starvation-induced autophagy. J. Biol. Chem. 291, 6026–6035 (2016).

    Article  CAS  Google Scholar 

  70. Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).

    Article  CAS  Google Scholar 

  71. Kim, Y. M. et al. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol. Cell 57, 207–218 (2015).

    Article  CAS  Google Scholar 

  72. Rousseau, A. & Bertolotti, A. An evolutionarily conserved pathway controls proteasome homeostasis. Nature 536, 184–189 (2016).

    Article  CAS  Google Scholar 

  73. Zhang, Y. et al. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513, 440–443 (2014).

    Article  CAS  Google Scholar 

  74. Pena-Llopis, S. et al. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30, 3242–3258 (2011).

    Article  CAS  Google Scholar 

  75. Alesi, N. et al. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nat. Commun. 12, 4245 (2021).

    Article  CAS  Google Scholar 

  76. Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).

    Article  CAS  Google Scholar 

  77. Bork, T. et al. Podocytes maintain high basal levels of autophagy independent of mtor signaling. Autophagy 16, 1932–1948 (2020).

    Article  CAS  Google Scholar 

  78. Hudson, E. R. et al. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr. Biol. 13, 861–866 (2003).

    Article  CAS  Google Scholar 

  79. Polekhina, G. et al. AMPK beta subunit targets metabolic stress sensing to glycogen. Curr. Biol. 13, 867–871 (2003).

    Article  CAS  Google Scholar 

  80. Xiao, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496–500 (2007).

    Article  CAS  Google Scholar 

  81. Hawley, S. A. et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271, 27879–27887 (1996).

    Article  CAS  Google Scholar 

  82. Scott, J. W. et al. Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chem. Biol. 21, 619–627 (2014).

    Article  CAS  Google Scholar 

  83. Hawley, S. A. et al. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19 (2005).

    Article  CAS  Google Scholar 

  84. Momcilovic, M., Hong, S.-P. & Carlson, M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro*. J. Biol. Chem. 281, 25336–25343 (2006).

    Article  CAS  Google Scholar 

  85. Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).

    Article  CAS  Google Scholar 

  86. Xiao, B. et al. Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233 (2011).

    Article  CAS  Google Scholar 

  87. Oakhill, J. S. et al. AMPK is a direct adenylate charge-regulated protein kinase. Science 332, 1433–1435 (2011).

    Article  CAS  Google Scholar 

  88. Hsu, C.-C. et al. Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK. Mol. Cell 81, 3803–3819.e3807 (2021).

    Article  CAS  Google Scholar 

  89. Zhang, C. S. et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548, 112–116 (2017).

    Article  CAS  Google Scholar 

  90. Li, M. et al. Transient receptor potential V channels are essential for glucose sensing by aldolase and AMPK. Cell Metab. 30, 508–524.e512 (2019).

    Article  CAS  Google Scholar 

  91. Zhang, Y. L. et al. AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metab. 18, 546–555 (2013).

    Article  CAS  Google Scholar 

  92. Zhang, C. S. et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 20, 526–540 (2014).

    Article  CAS  Google Scholar 

  93. Lin, S. C. & Hardie, D. G. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 27, 299–313 (2018).

    Article  CAS  Google Scholar 

  94. Horman, S. et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase α-subunits in heart via hierarchical phosphorylation of Ser485/491*. J. Biol. Chem. 281, 5335–5340 (2006).

    Article  CAS  Google Scholar 

  95. Loffler, A. S. et al. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 7, 696–706 (2011).

    Article  Google Scholar 

  96. Hawley, S. A. et al. Phosphorylation by Akt within the ST loop of AMPK-alpha1 down-regulates its activation in tumour cells. Biochem. J. 459, 275–287 (2014).

    Article  CAS  Google Scholar 

  97. Suzuki, T. et al. Inhibition of AMPK catabolic action by GSK3. Mol. Cell 50, 407–419 (2013).

    Article  CAS  Google Scholar 

  98. Ling, N. X. Y. et al. mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress. Nat. Metab. 2, 41–49 (2020).

    Article  CAS  Google Scholar 

  99. Auciello, F. R., Ross, F. A., Ikematsu, N. & Hardie, D. G. Oxidative stress activates AMPK in cultured cells primarily by increasing cellular AMP and/or ADP. FEBS Lett. 588, 3361–3366 (2014).

    Article  CAS  Google Scholar 

  100. Hart, P. C. et al. MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat. Commun. 6, 6053 (2015).

    Article  CAS  Google Scholar 

  101. Emerling, B. M. et al. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free. Radic. Biol. Med. 46, 1386–1391 (2009).

    Article  CAS  Google Scholar 

  102. Shao, D. et al. A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation. Cell Metab. 19, 232–245 (2014).

    Article  CAS  Google Scholar 

  103. Jeon, S. M. Regulation and function of AMPK in physiology and diseases. Exp. Mol. Med. 48, e245 (2016).

    Article  CAS  Google Scholar 

  104. Fullerton, M. D. et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649–1654 (2013).

    Article  CAS  Google Scholar 

  105. Wolfgang, M. J. et al. The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc. Natl Acad. Sci. USA 103, 7282–7287 (2006).

    Article  CAS  Google Scholar 

  106. Minokoshi, Y. et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002).

    Article  CAS  Google Scholar 

  107. Sato, R., Goldstein, J. L. & Brown, M. S. Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc. Natl Acad. Sci. Usa. 90, 9261–9265 (1993).

    Article  CAS  Google Scholar 

  108. Li, Y. et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 13, 376–388 (2011).

    Article  CAS  Google Scholar 

  109. Ahmadian, M. et al. Desnutrin/ATGL is regulated by AMPK and is required for a Brown Adipose Phenotype. Cell Metab. 13, 739–748 (2011).

    Article  CAS  Google Scholar 

  110. Wu, N. et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 49, 1167–1175 (2013).

    Article  CAS  Google Scholar 

  111. Marsin, A. S. et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 10, 1247–1255 (2000).

    Article  CAS  Google Scholar 

  112. Marsin, A.-S., Bouzin, C., Bertrand, L. & Hue, L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase *. J. Biol. Chem. 277, 30778–30783 (2002).

    Article  CAS  Google Scholar 

  113. Koo, S. H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005).

    Article  CAS  Google Scholar 

  114. Browne, G. J., Finn, S. G. & Proud, C. G. Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J. Biol. Chem. 279, 12220–12231 (2004).

    Article  CAS  Google Scholar 

  115. Choo, A. Y. et al. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol. Cell 38, 487–499 (2010).

    Article  CAS  Google Scholar 

  116. Kitada, M. & Koya, D. Autophagy in metabolic disease and ageing. Nat. Rev. Endocrinol. 17, 647–661 (2021).

    Article  Google Scholar 

  117. Kim, J., Kundu, M., Viollet, B. & Guan, K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

    Article  CAS  Google Scholar 

  118. Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

    Article  CAS  Google Scholar 

  119. Kim, J. et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290–303 (2013).

    Article  CAS  Google Scholar 

  120. Paquette, M. et al. AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3. Autophagy 17, 3957–3975 (2021).

    Article  CAS  Google Scholar 

  121. Russell, R. C. et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741–750 (2013).

    Article  CAS  Google Scholar 

  122. Egan, D. F. et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol. Cell 59, 285–297 (2015).

    Article  CAS  Google Scholar 

  123. Backer, J. M. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem. J. 410, 1–17 (2008).

    Article  CAS  Google Scholar 

  124. Backer, J. M. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem. J. 473, 2251–2271 (2016).

    Article  CAS  Google Scholar 

  125. Puertollano, R., Ferguson, S. M., Brugarolas, J. & Ballabio, A. The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. EMBO J. https://doi.org/10.15252/embj.201798804 (2018).

    Article  Google Scholar 

  126. Li, X. et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol. Cell 66, 684–697 e689 (2017).

    Article  CAS  Google Scholar 

  127. Shin, H.-J. R. et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 534, 553 (2016). +.

    Article  CAS  Google Scholar 

  128. Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).

    Article  CAS  Google Scholar 

  129. Tang, C. et al. Mitochondrial quality control in kidney injury and repair. Nat. Rev. Nephrol. 17, 299–318 (2021).

    Article  CAS  Google Scholar 

  130. Zong, H. et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl Acad. Sci. USA 99, 15983–15987 (2002).

    Article  CAS  Google Scholar 

  131. Jäger, S., Handschin, C., St.-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Article  Google Scholar 

  132. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  Google Scholar 

  133. Larsson, N. G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18, 231–236 (1998).

    Article  CAS  Google Scholar 

  134. Bergeron, R. et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. Endocrinol. Metab. 281, E1340–E1346 (2001).

    Article  CAS  Google Scholar 

  135. Garcia-Roves, P. M., Osler, M. E., Holmström, M. H. & Zierath, J. R. Gain-of-function R225Q mutation in AMP-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J. Biol. Chem. 283, 35724–35734 (2008).

    Article  CAS  Google Scholar 

  136. Sprenger, H.-G. & Langer, T. The good and the bad of mitochondrial breakups. Trends Cell Biol. 29, 888–900 (2019).

    Article  CAS  Google Scholar 

  137. Wai, T. & Langer, T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol. Metab. 27, 105–117 (2016).

    Article  CAS  Google Scholar 

  138. Toyama, E. Q. et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275–281 (2016).

    Article  CAS  Google Scholar 

  139. Otera, H. et al. Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J. Cell Biol. 191, 1141–1158 (2010).

    Article  CAS  Google Scholar 

  140. Chen, Z. et al. Global phosphoproteomic analysis reveals ARMC10 as an AMPK substrate that regulates mitochondrial dynamics. Nat. Commun. 10, 104 (2019).

    Article  Google Scholar 

  141. Hoffman, N. J. et al. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab. 22, 922–935 (2015).

    Article  CAS  Google Scholar 

  142. Gomes, L. C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589 (2011).

    Article  CAS  Google Scholar 

  143. Zhao, P. et al. An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science 367, 652–660 (2020).

    Article  CAS  Google Scholar 

  144. Godefroy, N., Foveau, B., Albrecht, S., Goodyer, C. G. & LeBlanc, A. C. Expression and activation of caspase-6 in human fetal and adult tissues. PLoS One 8, e79313 (2013).

    Article  CAS  Google Scholar 

  145. Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).

    Article  Google Scholar 

  146. Torres, J. A. et al. Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease. J. Clin. Invest. 129, 4506–4522 (2019).

    Article  Google Scholar 

  147. Novalic, Z. et al. Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease. J. Am. Soc. Nephrol. 23, 842–853 (2012).

    Article  CAS  Google Scholar 

  148. Inoki, K. et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest. 121, 2181–2196 (2011).

    Article  CAS  Google Scholar 

  149. Fischer, D. C. et al. Activation of the AKT/mTOR pathway in autosomal recessive polycystic kidney disease (ARPKD). Nephrol. Dial. Transpl. 24, 1819–1827 (2009).

    Article  CAS  Google Scholar 

  150. Ravichandran, K. et al. An mTOR anti-sense oligonucleotide decreases polycystic kidney disease in mice with a targeted mutation in Pkd2. Hum. Mol. Genet. 23, 4919–4931 (2014).

    Article  CAS  Google Scholar 

  151. Kim, S. et al. The polycystin complex mediates Wnt/Ca2+ signalling. Nat. Cell Biol. 18, 752–764 (2016).

    Article  CAS  Google Scholar 

  152. Kim, I. et al. Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J. Am. Soc. Nephrol. 19, 455–468 (2008).

    Article  CAS  Google Scholar 

  153. Kaffe, E. et al. beta-Catenin and interleukin-1beta-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. Hepatology 67, 1903–1919 (2018).

    Article  CAS  Google Scholar 

  154. Brook-Carter, P. T. et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease — a contiguous gene syndrome. Nat. Genet. 8, 328–332 (1994).

    Article  CAS  Google Scholar 

  155. Shillingford, J. M. et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl Acad. Sci. USA 103, 5466–5471 (2006).

    Article  CAS  Google Scholar 

  156. Dere, R., Wilson, P. D., Sandford, R. N. & Walker, C. L. Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. PLoS One 5, e9239 (2010).

    Article  Google Scholar 

  157. Zafar, I., Ravichandran, K., Belibi, F. A., Doctor, R. B. & Edelstein, C. L. Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease. Kidney Int. 78, 754–761 (2010).

    Article  CAS  Google Scholar 

  158. Wahl, P. R. et al. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol. Dial. Transpl. 21, 598–604 (2006).

    Article  CAS  Google Scholar 

  159. Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830–840 (2010).

    Article  CAS  Google Scholar 

  160. Serra, A. L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820–829 (2010).

    Article  CAS  Google Scholar 

  161. Yamahara, K. et al. Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J. Am. Soc. Nephrol. 24, 1769–1781 (2013).

    Article  CAS  Google Scholar 

  162. Brinkkoetter, P. T. et al. Anaerobic glycolysis maintains the glomerular filtration barrier independent of mitochondrial metabolism and dynamics. Cell Rep. 27, 1551–1566.e1555 (2019).

    Article  CAS  Google Scholar 

  163. Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).

    Article  CAS  Google Scholar 

  164. Sas, K. M. et al. Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications. JCI Insight 1, e86976 (2016).

    Article  Google Scholar 

  165. Wang, Z. et al. Spatial-resolved metabolomics reveals tissue-specific metabolic reprogramming in diabetic nephropathy by using mass spectrometry imaging. Acta Pharm. Sin. B 11, 3665–3677 (2021).

    Article  CAS  Google Scholar 

  166. Soliman, G. A. The integral role of mTOR in lipid metabolism. Cell Cycle 10, 861–862 (2011).

    Article  CAS  Google Scholar 

  167. Kogot-Levin, A. et al. Proximal tubule mTORC1 is a central player in the pathophysiology of diabetic nephropathy and its correction by SGLT2 inhibitors. Cell Rep. 32, 107954 (2020).

    Article  CAS  Google Scholar 

  168. Grahammer, F. et al. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proc. Natl Acad. Sci. USA 111, E2817–E2826 (2014).

    Article  CAS  Google Scholar 

  169. Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol. 12, 587–609 (2016).

    Article  CAS  Google Scholar 

  170. Fukuda, A. et al. Growth-dependent podocyte failure causes glomerulosclerosis. J. Am. Soc. Nephrol. 23, 1351–1363 (2012).

    Article  CAS  Google Scholar 

  171. Nishizono, R. et al. FSGS as an adaptive response to growth-induced podocyte stress. J. Am. Soc. Nephrol. 28, 2931–2945 (2017).

    Article  CAS  Google Scholar 

  172. Guzman, J. et al. Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy. Diabetes 63, 701–714 (2014).

    Article  CAS  Google Scholar 

  173. Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010).

    Article  CAS  Google Scholar 

  174. Chen, J. K., Chen, J., Thomas, G., Kozma, S. C. & Harris, R. C. S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophy. Am. J. Physiol. Renal Physiol. 297, F585–F593 (2009).

    Article  CAS  Google Scholar 

  175. Bonucci, M. et al. mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division. Nat. Commun. 11, 3200 (2020).

    Article  Google Scholar 

  176. Rajani, R., Pastor-Soler, N. M. & Hallows, K. R. Role of AMP-activated protein kinase in kidney tubular transport, metabolism, and disease. Curr. Opin. Nephrol. Hypertens. 26, 375–383 (2017).

    Article  CAS  Google Scholar 

  177. Hallows, K. R., Mount, P. F., Pastor-Soler, N. M. & Power, D. A. Role of the energy sensor AMP-activated protein kinase in renal physiology and disease. Am. J. Physiol. Renal Physiol. 298, F1067–F1077 (2010).

    Article  CAS  Google Scholar 

  178. proteinatlas. Tissue Cell Type — PRKAA1 — The Human Protein Atlas https://www.proteinatlas.org/ENSG00000132356-PRKAA1/tissue+cell+type/kidney (2021).

  179. Fraser, S. et al. Regulation of the energy sensor AMP-activated protein kinase in the kidney by dietary salt intake and osmolality. Am. J. Physiol. Renal Physiol. 288, F578–F586 (2005).

    Article  CAS  Google Scholar 

  180. Declèves, A.-E., Mathew, A. V., Cunard, R. & Sharma, K. AMPK mediates the initiation of kidney disease induced by a high-fat diet. J. Am. Soc. Nephrol. 22, 1846–1855 (2011).

    Article  Google Scholar 

  181. Kitada, M., Kume, S., Imaizumi, N. & Koya, D. Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes 60, 634–643 (2011).

    Article  CAS  Google Scholar 

  182. Lee, M.-J. et al. A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. Am. J. Physiol. Renal Physiol. 292, F617–F627 (2007).

    Article  CAS  Google Scholar 

  183. Balzer, M. S., Rohacs, T. & Susztak, K. How many cell types are in the kidney and what do they do? Annu. Rev. Physiol. 84, 507–531 (2022).

    Article  Google Scholar 

  184. Sharma, K. et al. Adiponectin regulates albuminuria and podocyte function in mice. J. Clin. Invest. 118, 1645–1656 (2008).

    CAS  Google Scholar 

  185. Kume, S. et al. Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J. Am. Soc. Nephrol. 18, 2715–2723 (2007).

    Article  CAS  Google Scholar 

  186. Han, S. H. et al. Deletion of Lkb1 in renal tubular epithelial cells leads to CKD by altering metabolism. J. Am. Soc. Nephrol. 27, 439–453 (2016).

    Article  CAS  Google Scholar 

  187. Lazo-Fernandez, Y. et al. Kidney-specific genetic deletion of both AMPK alpha-subunits causes salt and water wasting. Am. J. Physiol. Renal Physiol. 312, F352–F365 (2017).

    Article  CAS  Google Scholar 

  188. Yang, X. et al. Physiological expression of AMPKgamma2RG mutation causes Wolff-Parkinson-white syndrome and induces kidney injury in mice. J. Biol. Chem. 291, 23428–23439 (2016).

    Article  CAS  Google Scholar 

  189. Wilson, L. et al. Chronic activation of AMP-activated protein kinase leads to early-onset polycystic kidney phenotype. Clin. Sci. 135, 2393–2408 (2021).

    Article  CAS  Google Scholar 

  190. Chiaravalli, M. et al. 2-Deoxy-d-Glucose ameliorates PKD progression. J. Am. Soc. Nephrol. 27, 1958–1969 (2016).

    Article  CAS  Google Scholar 

  191. Rowe, I. et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 19, 488–493 (2013).

    Article  CAS  Google Scholar 

  192. Calcagni, A. et al. Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling. Elife https://doi.org/10.7554/eLife.17047 (2016).

    Article  Google Scholar 

  193. Tang, C., Livingston, M. J., Liu, Z. & Dong, Z. Autophagy in kidney homeostasis and disease. Nat. Rev. Nephrol. 16, 489–508 (2020).

    Article  CAS  Google Scholar 

  194. Choi, M. E. Autophagy in kidney disease. Annu. Rev. Physiol. 82, 297–322 (2020).

    Article  CAS  Google Scholar 

  195. Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011).

    Article  CAS  Google Scholar 

  196. Sakai, S. et al. Proximal tubule autophagy differs in type 1 and 2 diabetes. J. Am. Soc. Nephrol. 30, 929–945 (2019).

    Article  CAS  Google Scholar 

  197. Nagai, K. et al. Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Kidney Int. 68, 552–561 (2005).

    Article  CAS  Google Scholar 

  198. Sakaguchi, M. et al. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem. Biophys. Res. Commun. 340, 296–301 (2006).

    Article  CAS  Google Scholar 

  199. Lloberas, N. et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J. Am. Soc. Nephrol. 17, 1395–1404 (2006).

    Article  CAS  Google Scholar 

  200. Yao, Y. et al. Role of ragulator in the regulation of mechanistic target of rapamycin signaling in podocytes and glomerular function. J. Am. Soc. Nephrol. 27, 3653–3665 (2016).

    Article  CAS  Google Scholar 

  201. Mori, H. et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem. Biophys. Res. Commun. 384, 471–475 (2009).

    Article  CAS  Google Scholar 

  202. Tomita, I. et al. SGLT2 Inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab. 32, 404–419 e406 (2020).

    Article  CAS  Google Scholar 

  203. Torras, J. et al. Rapamycin has dual opposing effects on proteinuric experimental nephropathies: is it a matter of podocyte damage. Nephrol. Dial. Transpl. 24, 3632–3640 (2009).

    Article  CAS  Google Scholar 

  204. Letavernier, E. et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin. J. Am. Soc. Nephrol. 2, 326–333 (2007).

    Article  CAS  Google Scholar 

  205. Oleksak, P. et al. Contemporary mTOR inhibitor scaffolds to diseases breakdown: a patent review (2015-2021). Eur. J. Med. Chem. 238, 114498 (2022).

    Article  CAS  Google Scholar 

  206. Eid, A. et al. Intrinsic gluconeogenesis is enhanced in renal proximal tubules of Zucker diabetic fatty rats. J. Am. Soc. Nephrol. 17, 398–405 (2006).

    Article  CAS  Google Scholar 

  207. Gerich, J. E., Meyer, C., Woerle, H. J. & Stumvoll, M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24, 382–391 (2001).

    Article  CAS  Google Scholar 

  208. Bridges, H. R., Jones, A. J., Pollak, M. N. & Hirst, J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 462, 475–487 (2014).

    Article  CAS  Google Scholar 

  209. Dykens, J. A. et al. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol. 233, 203–210 (2008).

    Article  CAS  Google Scholar 

  210. Wilcock, C. & Bailey, C. J. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24, 49–57 (1994).

    Article  CAS  Google Scholar 

  211. LaMoia, T. E. & Shulman, G. I. Cellular and molecular mechanisms of metformin action. Endocr. Rev. 42, 77–96 (2021).

    Article  Google Scholar 

  212. Ma, T. et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature https://doi.org/10.1038/s41586-022-04431-8 (2022).

    Article  Google Scholar 

  213. Wang, Y. et al. Metformin improves mitochondrial respiratory activity through activation of AMPK. Cell Rep. 29, 1511–1523 e1515 (2019).

    Article  CAS  Google Scholar 

  214. Howell, J. J. et al. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 25, 463–471 (2017).

    Article  CAS  Google Scholar 

  215. Stein, B. D. et al. Quantitative in vivo proteomics of metformin response in liver reveals AMPK-dependent and -independent signaling networks. Cell Rep. 29, 3331–3348 e3337 (2019).

    Article  CAS  Google Scholar 

  216. LaMoia, T. E. et al. Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proc. Natl Acad. Sci. USA 119, e2122287119 (2022).

    Article  CAS  Google Scholar 

  217. Zhang, C. S. et al. Metformin activates AMPK through the lysosomal pathway. Cell Metab. 24, 521–522 (2016).

    Article  Google Scholar 

  218. Takiar, V. et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl Acad. Sci. USA 108, 2462–2467 (2011).

    Article  CAS  Google Scholar 

  219. Myers, R. W. et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science 357, 507–511 (2017).

    Article  CAS  Google Scholar 

  220. Esquejo, R. M. et al. Activation of liver AMPK with PF-06409577 corrects NAFLD and lowers cholesterol in rodent and primate preclinical models. EBioMedicine 31, 122–132 (2018).

    Article  Google Scholar 

  221. Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).

    Article  CAS  Google Scholar 

  222. Zhou, X. et al. PAN-AMPK activation improves renal function in a rat model of progressive diabetic nephropathy. J. Pharmacol. Exp. Ther. 371, 45–55 (2019).

    Article  CAS  Google Scholar 

  223. Salatto, C. T. et al. Selective activation of AMPK β1-containing isoforms improves kidney function in a rat model of diabetic nephropathy. J. Pharmacol. Exp. Ther. 361, 303–311 (2017).

    Article  CAS  Google Scholar 

  224. Lieberthal, W., Tang, M., Lusco, M., Abate, M. & Levine, J. S. Preconditioning mice with activators of AMPK ameliorates ischemic acute kidney injury in vivo. Am. J. Physiol. Renal Physiol. 311, F731–F739 (2016).

    Article  CAS  Google Scholar 

  225. Ghezzi, C., Loo, D. D. F. & Wright, E. M. Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia 61, 2087–2097 (2018).

    Article  CAS  Google Scholar 

  226. DeFronzo, R. A., Norton, L. & Abdul-Ghani, M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat. Rev. Nephrol. 13, 11–26 (2017).

    Article  CAS  Google Scholar 

  227. Thomson, S. C. et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R75–R83 (2012).

    Article  CAS  Google Scholar 

  228. Vallon, V. et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am. J. Physiol. Renal Physiol. 306, F194–F204 (2014).

    Article  CAS  Google Scholar 

  229. Striepe, K. et al. Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus. Circulation 136, 1167–1169 (2017).

    Article  CAS  Google Scholar 

  230. Verma, S. & McMurray, J. J. V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 61, 2108–2117 (2018).

    Article  CAS  Google Scholar 

  231. Al Jobori, H. et al. Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients. Diabetes Obes. Metab. 19, 809–813 (2017).

    Article  CAS  Google Scholar 

  232. Xie, Z. et al. Metabolic regulation of gene expression by histone lysine beta-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).

    Article  CAS  Google Scholar 

  233. Koronowski, K. B. et al. Ketogenesis impact on liver metabolism revealed by proteomics of lysine beta-hydroxybutyrylation. Cell Rep. 36, 109487 (2021).

    Article  CAS  Google Scholar 

  234. Xu, J., Kitada, M., Ogura, Y., Liu, H. & Koya, D. Dapagliflozin restores impaired autophagy and suppresses inflammation in high glucose-treated HK-2 cells. Cells https://doi.org/10.3390/cells10061457 (2021).

    Article  Google Scholar 

  235. Packer, M. Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: a novel conceptual framework. Diabetes Obes. Metab. 22, 734–742 (2020).

    Article  CAS  Google Scholar 

  236. Hawley, S. A. et al. The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes 65, 2784–2794 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors’ work is supported by National Institute of Health (NIH) RO1 grants (DK124709 and GM145631) to K. I.

Author information

Author notes

  1. These authors contributed equally: Jaewhee Ryu, Jooho Lee and Ayaka Inoki.

Authors and Affiliations

  1. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Christopher Huynh, Jaewhee Ryu, Jooho Lee & Ken Inoki

  2. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Christopher Huynh & Ken Inoki

  3. Department of Biology, Johns Hopkins University, Baltimore, MD, USA

    Ayaka Inoki

  4. Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, USA

    Ayaka Inoki & Ken Inoki

Authors
  1. Christopher Huynh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaewhee Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jooho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayaka Inoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ken Inoki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission. K.I. and C.H. made substantial contributions to discussion of the content.

Corresponding author

Correspondence to Ken Inoki.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Frugivores

Animals that subsist totally or primarily on fruit.

Michaelis constant (Km)

The substrate concentration at which half of the maximum reaction rate is achieved.

Mitophagy

Selective removal of damaged mitochondria by the autophagic machinery.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-022-00648-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research