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Autophagy in kidney homeostasis and disease

Nature Reviews Nephrology volume 16, pages 489–508 (2020)Cite this article

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Abstract

Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic components. Basal autophagy in kidney cells is essential for the maintenance of kidney homeostasis, structure and function. Under stress conditions, autophagy is altered as part of the adaptive response of kidney cells, in a process that is tightly regulated by signalling pathways that can modulate the cellular autophagic flux — mammalian target of rapamycin, AMP-activated protein kinase and sirtuins are key regulators of autophagy. Dysregulated autophagy contributes to the pathogenesis of acute kidney injury, to incomplete kidney repair after acute kidney injury and to chronic kidney disease of varied aetiologies, including diabetic kidney disease, focal segmental glomerulosclerosis and polycystic kidney disease. Autophagy also has a role in kidney ageing. However, questions remain about whether autophagy has a protective or a pathological role in kidney fibrosis, and about the precise mechanisms and signalling pathways underlying the autophagy response in different types of kidney cells and across the spectrum of kidney diseases. Further research is needed to gain insights into the regulation of autophagy in the kidneys and to enable the discovery of pathway-specific and kidney-selective therapies for kidney diseases and anti-ageing strategies.

Key points

  • Basal autophagy is essential to the maintenance of kidney homeostasis, structure and function.

  • Autophagy is suppressed in aged kidneys, which accelerates the progression of ageing and age-related kidney diseases.

  • In the acute injury phase of acute kidney injury (AKI), autophagy is induced in proximal tubules and acts as a protective mechanism. During the recovery phase, regulated autophagy is crucial for tubular repair.

  • Persistent activation of autophagy after AKI induces phenotypic changes in proximal tubule cells that might lead to maladaptive repair, contribute to interstitial fibrosis and promote transition from AKI to chronic kidney disease.

  • Autophagy defects in kidney cells of both tubular and glomerular compartments contribute to the development of diabetic kidney disease and focal segmental glomerulosclerosis.

  • Polycystic kidney disease is associated with autophagy defects in kidney tubules that might contribute to the development and formation of kidney cysts.

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Fig. 1: Autophagy dynamics and core machinery.
Fig. 2: Mitophagy pathways and cargo recognition.
Fig. 3: Signalling networks for the induction of autophagy.
Fig. 4: Autophagy in AKI and kidney interstitial fibrosis.
Fig. 5: Autophagy in diabetic kidney disease.

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References

  1. Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Oku, M. & Sakai, Y. Three distinct types of microautophagy based on membrane dynamics and molecular machineries. Bioessays 40, e1800008 (2018).

    Article  PubMed  Google Scholar 

  3. Kaushik, S. & Cuervo, A. M. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 19, 365–381 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Morishita, H. & Mizushima, N. Diverse cellular roles of autophagy. Annu. Rev. Cell Dev. Biol. 35, 453–475 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Park, J. M. et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547–564 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Park, J. M. et al. ULK1 phosphorylates Ser30 of BECN1 in association with ATG14 to stimulate autophagy induction. Autophagy 14, 584–597 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Zachari, M. & Ganley, I. G. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 61, 585–596 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  9. Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519–530 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Zhong, Y. et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat. Cell Biol. 11, 468–476 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Walczak, M. & Martens, S. Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation. Autophagy 9, 424–425 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Lorincz, P. & Juhasz, G. Autophagosome-lysosome fusion. J. Mol. Biol. 432, 2462–2482 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Gatica, D., Lahiri, V. & Klionsky, D. J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol. 20, 233–242 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. 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  PubMed  PubMed Central  Google Scholar 

  16. 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  PubMed Central  PubMed  Google Scholar 

  17. 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  PubMed Central  PubMed  Google Scholar 

  18. Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487–511 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Chang, K. et al. TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy https://doi.org/10.1080/15548627.2019.1704117 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  20. Aspernig, H. et al. Mitochondrial perturbations couple mTORC2 to autophagy in C. elegans. Cell Rep. 29, 1399–1409 e1395 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Herrero-Martin, G. et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J. 28, 677–685 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Anderson, K. A. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Lee, J. W., Park, S., Takahashi, Y. & Wang, H. G. The association of AMPK with ULK1 regulates autophagy. PLoS One 5, e15394 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Dunlop, E. A., Hunt, D. K., Acosta-Jaquez, H. A., Fingar, D. C. & Tee, A. R. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7, 737–747 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Kim, J., Yang, G., Kim, Y., Kim, J. & Ha, J. AMPK activators: mechanisms of action and physiological activities. Exp. Mol. Med. 48, e224 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Lee, I. H. et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl Acad. Sci. USA 105, 3374–3379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang, R. et al. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol. Cell 57, 456–466 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Hariharan, N. et al. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ. Res. 107, 1470–1482 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lan, F., Cacicedo, J. M., Ruderman, N. & Ido, Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283, 27628–27635 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Hou, X. et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283, 20015–20026 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Ghosh, H. S., McBurney, M. & Robbins, P. D. SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One 5, e9199 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Dai, H., Sinclair, D. A., Ellis, J. L. & Steegborn, C. Sirtuin activators and inhibitors: promises, achievements, and challenges. Pharmacol. Ther. 188, 140–154 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Wei, Y., Pattingre, S., Sinha, S., Bassik, M. & Levine, B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol. Cell 30, 678–688 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Zalckvar, E. et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep. 10, 285–292 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. B’Chir, W. et al. The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 41, 7683–7699 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Criollo, A. et al. The IKK complex contributes to the induction of autophagy. EMBO J. 29, 619–631 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Chauhan, S. et al. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol. Cell 50, 16–28 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Liu, S. et al. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8, 826–837 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. 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  PubMed Central  PubMed  Google Scholar 

  45. Kim, S. I. et al. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J. Biol. Chem. 287, 11677–11688 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Ding, Y. et al. TGF-{beta}1 protects against mesangial cell apoptosis via induction of autophagy. J. Biol. Chem. 285, 37909–37919 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Bechtel, W. et al. Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis. J. Am. Soc. Nephrol. 24, 727–743 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Chen, J., Chen, M. X., Fogo, A. B., Harris, R. C. & Chen, J. K. mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J. Am. Soc. Nephrol. 24, 198–207 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Cina, D. P. et al. Inhibition of MTOR disrupts autophagic flux in podocytes. J. Am. Soc. Nephrol. 23, 412–420 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Oshima, Y. et al. Prorenin receptor is essential for normal podocyte structure and function. J. Am. Soc. Nephrol. 22, 2203–2212 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. 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  PubMed Central  CAS  PubMed  Google Scholar 

  52. 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  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Rong, Y. et al. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc. Natl Acad. Sci. USA 108, 7826–7831 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bork, T. et al. Podocytes maintain high basal levels of autophagy independent of mtor signaling. Autophagy https://doi.org/10.1080/15548627.2019.1705007 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  56. Alghamdi, T. A. et al. Janus kinase 2 regulates transcription factor EB expression and autophagy completion in glomerular podocytes. J. Am. Soc. Nephrol. 28, 2641–2653 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. 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  PubMed Central  PubMed  Google Scholar 

  58. Livingston, M. J. et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy 15, 2142–2162 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. McWilliams, T. G. et al. mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J. Cell Biol. 214, 333–345 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Lenoir, O. et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy 11, 1130–1145 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Matsuda, J. et al. Antioxidant role of autophagy in maintaining the integrity of glomerular capillaries. Autophagy 14, 53–65 (2018).

    Article  CAS  PubMed  Google Scholar 

  62. O’Sullivan, E. D., Hughes, J. & Ferenbach, D. A. Renal aging: causes and consequences. J. Am. Soc. Nephrol. 28, 407–420 (2017).

    Article  PubMed  Google Scholar 

  63. Nakamura, S. et al. Suppression of autophagic activity by Rubicon is a signature of aging. Nat. Commun. 10, 847 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Cui, J. et al. Age-related changes in the function of autophagy in rat kidneys. Age 34, 329–339 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Yamamoto-Nonaka, K. et al. Cathepsin D in podocytes is important in the pathogenesis of proteinuria and CKD. J. Am. Soc. Nephrol. 27, 2685–2700 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Chuang, P. Y. et al. Reduction in podocyte SIRT1 accelerates kidney injury in aging mice. Am. J. Physiol. Renal Physiol. 313, F621–F628 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Zhang, L. et al. C/EBPalpha deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice. Cell Death Dis. 10, 684 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Yamamoto, T. et al. Time-dependent dysregulation of autophagy: implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 12, 801–813 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Kaushal, G. P. & Shah, S. V. Autophagy in acute kidney injury. Kidney Int. 89, 779–791 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Jiang, M. et al. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 82, 1271–1283 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Takahashi, A. et al. Autophagy guards against cisplatin-induced acute kidney injury. Am. J. Pathol. 180, 517–525 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Hsiao, H. W. et al. The decline of autophagy contributes to proximal tubular dysfunction during sepsis. Shock 37, 289–296 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Leventhal, J. S. et al. Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression. PloS One 11, e0150001 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Mei, S. et al. Autophagy is activated to protect against endotoxic acute kidney injury. Sci. Rep. 6, 22171 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Howell, G. M. et al. Augmenting autophagy to treat acute kidney injury during endotoxemia in mice. PloS One 8, e69520 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Ko, G. J., Bae, S. Y., Hong, Y. A., Pyo, H. J. & Kwon, Y. J. Radiocontrast-induced nephropathy is attenuated by autophagy through regulation of apoptosis and inflammation. Hum. Exp. Toxicol. 35, 724–736 (2016).

    Article  CAS  PubMed  Google Scholar 

  77. Lin, Q. et al. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol. 26, 101254 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Lei, R. et al. Mitophagy plays a protective role in iodinated contrast-induced acute renal tubular epithelial cells injury. Cell Physiol. Biochem. 46, 975–985 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Lempiainen, J. et al. Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1alpha-eNOS pathway and enhanced autophagy. Acta Physiol. 208, 410–421 (2013).

    Article  CAS  Google Scholar 

  80. 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  PubMed  PubMed Central  Google Scholar 

  81. Chien, C. T., Shyue, S. K. & Lai, M. K. Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy. Transplantation 84, 1183–1190 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Rovetta, F. et al. ER signaling regulation drives the switch between autophagy and apoptosis in NRK-52E cells exposed to cisplatin. Exp. Cell Res. 318, 238–250 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Herzog, C., Yang, C., Holmes, A. & Kaushal, G. P. zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function. Am. J. Physiol. Renal Physiol. 303, F1239–F1250 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Jankauskas, S. S. et al. The age-associated loss of ischemic preconditioning in the kidney is accompanied by mitochondrial dysfunction, increased protein acetylation and decreased autophagy. Sci. Rep. 7, 44430 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Xie, Y. et al. Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway. Cell Death Dis. 9, 338 (2018).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Bhatia, D. & Choi, M. E. The emerging role of mitophagy in kidney diseases. J. Life Sci. 1, 13–22 (2019).

    Google Scholar 

  87. Wang, Y., Cai, J., Tang, C. & Dong, Z. Mitophagy in acute kidney injury and kidney repair. Cells 9, 338 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  88. Tang, C. et al. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 14, 880–897 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Tang, C. et al. Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury. Cell Death Dis. 10, 677 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Wang, Y. et al. PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury. Cell Death Dis. 9, 1113 (2018).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Zhao, C. et al. Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function. Oncotarget 8, 20988–21000 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  92. Liu, J. X. et al. Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury. Life Sci. 235, 116828 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Chang-Panesso, M. et al. FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury. J. Clin. Invest. 129, 5501–5517 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Kusaba, T., Lalli, M., Kramann, R., Kobayashi, A. & Humphreys, B. D. Differentiated kidney epithelial cells repair injured proximal tubule. Proc. Natl Acad. Sci. USA 111, 1527–1532 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Rosen, S. & Heyman, S. Concerning cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int. 94, 218 (2018).

    Article  PubMed  Google Scholar 

  97. Kumar, S. Cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int. 93, 27–40 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Li, L., Wang, Z. V., Hill, J. A. & Lin, F. New autophagy reporter mice reveal dynamics of proximal tubular autophagy. J. Am. Soc. Nephrol. 25, 305–315 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Cheng, H., Fan, X., Lawson, W. E., Paueksakon, P. & Harris, R. C. Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy. Kidney Int. 88, 85–94 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Nassour, J. et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature 565, 659–663 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Taji, F. et al. Autophagy induction reduces telomerase activity in HeLa cells. Mech. Ageing Dev. 163, 40–45 (2017).

    Article  CAS  PubMed  Google Scholar 

  102. Baisantry, A. et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J. Am. Soc. Nephrol. 27, 1609–1616 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V. & Bonventre, J. V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med. 16, 535–543 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Canaud, G. et al. Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair. Sci. Transl. Med. 11, eaav4754 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Li, L. et al. FoxO3 activation in hypoxic tubules prevents chronic kidney disease. J. Clin. Invest. 129, 2374–2389 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  106. Shu, S. et al. Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease. EBioMedicine 37, 269–280 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  107. Li, L., Zepeda-Orozco, D., Black, R. & Lin, F. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 176, 1767–1778 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Livingston, M. J. et al. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy 12, 976–998 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Yan, Q. et al. Autophagy activation contributes to lipid accumulation in tubular epithelial cells during kidney fibrosis. Cell Death Discov. 4, 2 (2018).

    PubMed  Google Scholar 

  110. Hernandez-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938–946 (2012).

    Article  PubMed  Google Scholar 

  111. Thoen, L. F. et al. A role for autophagy during hepatic stellate cell activation. J. Hepatol. 55, 1353–1360 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Xue, X. et al. Protein kinase Calpha drives fibroblast activation and kidney fibrosis by stimulating autophagic flux. J. Biol. Chem. 293, 11119–11130 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Li, L. et al. Forkhead box O3 (FoxO3) regulates kidney tubular autophagy following urinary tract obstruction. J. Biol. Chem. 292, 13774–13783 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Yang, X. et al. WNT1-inducible signaling protein-1 mediates TGF-beta1-induced renal fibrosis in tubular epithelial cells and unilateral ureteral obstruction mouse models via autophagy. J. Cell Physiol. 235, 2009–2022 (2020).

    Article  CAS  PubMed  Google Scholar 

  115. Noh, M. R., Woo, C. H., Park, M. J., In Kim, J. & Park, K. M. Ablation of C/EBP homologous protein attenuates renal fibrosis after ureteral obstruction by reducing autophagy and microtubule disruption. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 1634–1641 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Kim, W. Y. et al. The role of autophagy in unilateral ureteral obstruction rat model. Nephrology 17, 148–159 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Xu, G. et al. Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. Aging 8, 977–985 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Ding, Y. et al. Autophagy regulates TGF-beta expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J. Am. Soc. Nephrol. 25, 2835–2846 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  119. Li, H. et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy 12, 1472–1486 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Peng, X. et al. ATG5-mediated autophagy suppresses NF-kappaB signaling to limit epithelial inflammatory response to kidney injury. Cell Death Dis. 10, 253 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Xu, Y., Wang, J., Xu, W., Ding, F. & Ding, W. Prohibitin 2-mediated mitophagy attenuates renal tubular epithelial cells injury by regulating mitochondrial dysfunction and NLRP3 inflammasome activation. Am. J. Physiol. Renal Physiol. 316, F396–F407 (2019).

    Article  PubMed  Google Scholar 

  122. Nam, S. A. et al. Autophagy in FOXD1 stroma-derived cells regulates renal fibrosis through TGF-beta and NLRP3 inflammasome pathway. Biochem. Biophys. Res. Commun. 508, 965–972 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Nam, S. A. et al. Autophagy attenuates tubulointerstital fibrosis through regulating transforming growth factor-beta and NLRP3 inflammasome signaling pathway. Cell Death Dis. 10, 78 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Bhatia, D. et al. Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis. JCI Insight 4, e132826 (2019).

    Article  PubMed Central  Google Scholar 

  125. Li, S. et al. Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction. Free Radic. Biol. Med. 152, 632–649 (2020).

    Article  CAS  PubMed  Google Scholar 

  126. Alicic, R. Z., Rooney, M. T. & Tuttle, K. R. Diabetic kidney disease: challenges, progress, and possibilities. Clin. J. Am. Soc. Nephrol. 12, 2032–2045 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Liu, W. J. et al. Lysosome restoration to activate podocyte autophagy: a new therapeutic strategy for diabetic kidney disease. Cell Death Dis. 10, 806 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Tagawa, A. et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65, 755–767 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Yang, D. et al. Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. Cell Mol. Life Sci. 75, 669–688 (2018).

    Article  CAS  PubMed  Google Scholar 

  130. Ding, Y. & Choi, M. E. Autophagy in diabetic nephropathy. J. Endocrinol. 224, R15–R30 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Zhao, X. et al. Advanced glycation end-products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB. J. Pathol. 245, 235–248 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Liu, J. et al. beta-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy. Cell Death Dis. 7, e2183 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  133. Wang, X. et al. Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int. 86, 712–725 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Li, W. et al. FoxO1 promotes mitophagy in the podocytes of diabetic male mice via the PINK1/Parkin pathway. Endocrinology 158, 2155–2167 (2017).

    Article  CAS  PubMed  Google Scholar 

  135. Zhou, D. et al. PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy. Cell Death Dis. 10, 524 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Wang, H. et al. Podocyte-specific knockin of PTEN protects kidney from hyperglycemia. Am. J. Physiol. Renal Physiol. 314, F1096–F1107 (2018).

    Article  CAS  PubMed  Google Scholar 

  137. Liu, M. et al. Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nat. Commun. 8, 413 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  138. Li, L. et al. Signal regulatory protein alpha protects podocytes through promoting autophagic activity. JCI Insight 5, e124747 (2019).

    Article  Google Scholar 

  139. Zhan, M., Usman, I. M., Sun, L. & Kanwar, Y. S. Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease. J. Am. Soc. Nephrol. 26, 1304–1321 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Ma, Z. et al. p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney. J. Clin. Invest. (in the press).

  141. Vallon, V. et al. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am. J. Physiol. Renal Physiol. 304, F156–F167 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Wang, Y., Zheng, Z. J., Jia, Y. J., Yang, Y. L. & Xue, Y. M. Role of p53/miR-155-5p/sirt1 loop in renal tubular injury of diabetic kidney disease. J. Transl. Med. 16, 146 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Zhang, Y. et al. MicroRNA-22 promotes renal tubulointerstitial fibrosis by targeting PTEN and suppressing autophagy in diabetic nephropathy. J. Diabetes Res. 2018, 4728645 (2018).

    PubMed Central  PubMed  Google Scholar 

  144. Huang, C. et al. Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway. Sci. Rep. 6, 29196 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  145. Chen, K. et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy. Cell Death Dis. 9, 105 (2018).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  146. Brijmohan, A. S. et al. HDAC6 inhibition promotes transcription factor EB activation and is protective in experimental kidney disease. Front. Pharmacol. 9, 34 (2018).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. Pontrelli, P. et al. Deregulation of autophagy under hyperglycemic conditions is dependent on increased lysine 63 ubiquitination: a candidate mechanism in the progression of diabetic nephropathy. J. Mol. Med. 96, 645–659 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Tan, J., Wang, M., Song, S., Miao, Y. & Zhang, Q. Autophagy activation promotes removal of damaged mitochondria and protects against renal tubular injury induced by albumin overload. Histol. Histopathol. 33, 681–690 (2018).

    CAS  PubMed  Google Scholar 

  150. Nolin, A. C. et al. Proteinuria causes dysfunctional autophagy in the proximal tubule. Am. J. Physiol. Renal Physiol. 311, F1271–F1279 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  151. Xu, D. et al. NIX-mediated mitophagy protects against proteinuria-induced tubular cell apoptosis and renal injury. Am. J. Physiol. Renal Physiol. 316, F382–F395 (2019).

    Article  PubMed  Google Scholar 

  152. Kitada, M. et al. Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes. Exp. Diabetes Res. 2011, 908185 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  153. Kitada, M. et al. A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity. Diabetologia 59, 1307–1317 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Saito, A. et al. Significance of proximal tubular metabolism of advanced glycation end products in kidney diseases. Ann. NY Acad. Sci. 1043, 637–643 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Takahashi, A. et al. Autophagy inhibits the accumulation of advanced glycation end products by promoting lysosomal biogenesis and function in the kidney proximal tubules. Diabetes 66, 1359–1372 (2017).

    Article  CAS  PubMed  Google Scholar 

  157. Liu, W. J. et al. Autophagy-lysosome pathway in renal tubular epithelial cells is disrupted by advanced glycation end products in diabetic nephropathy. J. Biol. Chem. 290, 20499–20510 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  158. Xavier, S. et al. BAMBI is expressed in endothelial cells and is regulated by lysosomal/autolysosomal degradation. PLoS One 5, e12995 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Fan, Y. et al. BAMBI elimination enhances alternative TGF-beta signaling and glomerular dysfunction in diabetic mice. Diabetes 64, 2220–2233 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Fiorentino, L. et al. Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol. Med. 5, 441–455 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  161. Xu, L., Fan, Q., Wang, X., Zhao, X. & Wang, L. Inhibition of autophagy increased AGE/ROS-mediated apoptosis in mesangial cells. Cell Death Dis. 7, e2445 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  162. Rosenberg, A. Z. & Kopp, J. B. Focal Segmental Glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 12, 502–517 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  163. Kumar, V. et al. Disrupted apolipoprotein L1-miR193a axis dedifferentiates podocytes through autophagy blockade in an APOL1 risk milieu. Am. J. Physiol. Cell Physiol. 317, C209–C225 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  164. Beckerman, P. et al. Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat. Med. 23, 429–438 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  165. Asanuma, K. et al. MAP-LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis. FASEB J. 17, 1165–1167 (2003).

    Article  CAS  PubMed  Google Scholar 

  166. Yi, M. et al. Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy. Am. J. Physiol. Renal Physiol. 313, F74–F84 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. Kawakami, T. et al. Deficient autophagy results in mitochondrial dysfunction and FSGS. J. Am. Soc. Nephrol. 26, 1040–1052 (2015).

    Article  CAS  PubMed  Google Scholar 

  168. Zeng, C. et al. Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies. J. Pathol. 234, 203–213 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Ogawa-Akiyama, A. et al. Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome. PLoS One 15, e0228337 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  171. Torres, V. E. & Harris, P. C. Progress in the understanding of polycystic kidney disease. Nat. Rev. Nephrol. 15, 70–72 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  172. Belibi, F. et al. Hypoxia-inducible factor-1alpha (HIF-1alpha) and autophagy in polycystic kidney disease (PKD). Am. J. Physiol. Renal Physiol. 300, F1235–F1243 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Nowak, K. L. & Edelstein, C. L. Apoptosis and autophagy in polycystic kidney disease (PKD). Cell. Signal. 68, 109518 (2020).

    Article  CAS  PubMed  Google Scholar 

  174. Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B. & Christensen, S. T. Cellular signalling by primary cilia in development, organ function and disease. Nat. Rev. Nephrol. 15, 199–219 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  175. Pampliega, O. & Cuervo, A. M. Autophagy and primary cilia: dual interplay. Curr. Opin. Cell Biol. 39, 1–7 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  176. Wang, S., Livingston, M. J., Su, Y. & Dong, Z. Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways. Autophagy 11, 607–616 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhu, P., Sieben, C. J., Xu, X., Harris, P. C. & Lin, X. Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model. Hum. Mol. Genet. 26, 158–172 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Cornec-Le Gall, E., Alam, A. & Perrone, R. D. Autosomal dominant polycystic kidney disease. Lancet 393, 919–935 (2019).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  182. Li, A. et al. Rapamycin treatment dose-dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell-cycle-associated CDK1/cyclin axis. J. Cell Mol. Med. 21, 1619–1635 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  183. Kou, P., Wei, S. & Xiong, F. Recent advances of mTOR inhibitors use in autosomal dominant polycystic kidney disease: is the road still open? Curr. Med. Chem. 26, 2962–2973 (2019).

    Article  CAS  PubMed  Google Scholar 

  184. Calvo-Rubio, M. et al. Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice. Aging Cell 15, 477–487 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  185. Shavlakadze, T. et al. Short-term low-dose mTORC1 inhibition in aged rats counter-regulates age-related gene changes and blocks age-related kidney pathology. J. Gerontol. A Biol. Sci. Med. Sci. 73, 845–852 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  186. Hong, Q. et al. Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int. 93, 1330–1343 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  187. Ren, H. et al. Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway. Mol. Cell Endocrinol. 500, 110628 (2020).

    Article  CAS  PubMed  Google Scholar 

  188. Li, X. Y. et al. Triptolide restores autophagy to alleviate diabetic renal fibrosis through the miR-141-3p/PTEN/Akt/mTOR pathway. Mol. Ther. Nucleic Acids 9, 48–56 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  189. Song, G. et al. Astragaloside IV ameliorates early diabetic nephropathy by inhibition of MEK1/2-ERK1/2-RSK2 signaling in streptozotocin-induced diabetic mice. J. Int. Med. Res. 46, 2883–2897 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  190. Guo, H. et al. Astragaloside IV protects against podocyte injury via SERCA2-dependent ER stress reduction and AMPKalpha-regulated autophagy induction in streptozotocin-induced diabetic nephropathy. Sci. Rep. 7, 6852 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  191. Wang, X. et al. Astragaloside IV represses high glucose-induced mesangial cells activation by enhancing autophagy via SIRT1 deacetylation of NF-kappaB p65 subunit. Drug Des. Devel. Ther. 12, 2971–2980 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  192. Morel, E. et al. Autophagy: a druggable process. Annu. Rev. Pharmacol. Toxicol. 57, 375–398 (2017).

    Article  CAS  PubMed  Google Scholar 

  193. Panda, P. K. et al. Chemical screening approaches enabling drug discovery of autophagy modulators for biomedical applications in human diseases. Front. Cell Dev. Biol. 7, 38 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  194. Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  195. Williams, A. et al. Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol. 4, 295–305 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  196. Lin, T. A., Wu, V. C. & Wang, C. Y. Autophagy in chronic kidney diseases. Cells 8, 61 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  197. Pasquier, B. Autophagy inhibitors. Cell Mol. Life Sci. 73, 985–1001 (2016).

    Article  CAS  PubMed  Google Scholar 

  198. 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  PubMed Central  PubMed  Google Scholar 

  199. Viana, S. D., Reis, F. & Alves, R. Therapeutic use of mTOR inhibitors in renal diseases: advances, drawbacks, and challenges. Oxid. Med. Cell Longev. 2018, 3693625 (2018).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  200. Larson-Casey, J. L., Deshane, J. S., Ryan, A. J., Thannickal, V. J. & Carter, A. B. Macrophage Akt1 kinase-mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis. Immunity 44, 582–596 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  201. Rinschen, M. M. et al. A multi-layered quantitative in vivo expression atlas of the podocyte unravels kidney disease candidate genes. Cell Rep. 23, 2495–2508 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

The authors were supported in part by grants from the National Natural Science Foundation of China (81870474), the National Institutes of Health (DK058831, DK087843) and the US Department of Veterans Affairs (BX000319). Z.D. is a recipient of the Senior Research Career Scientist award from the US Department of Veterans Affairs.

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Authors and Affiliations

  1. Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Second Xiangya Hospital at Central South University, Changsha, China

    Chengyuan Tang, Zhiwen Liu & Zheng Dong

  2. Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Man J. Livingston & Zheng Dong

  3. Charlie Norwood VA Medical Center, Augusta, GA, USA

    Zheng Dong

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C.T. and Z.D. researched data for the article and wrote the article. All authors contributed substantially to discussion of the content, and reviewed and edited the article before submission.

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Correspondence to Zheng Dong.

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Glossary

Vesicle nucleation

The process of mobilizing a small group of molecules to the phagophore assembly site to form a phagophore during autophagy.

Phagophore

A cup-shaped double-membrane vesicle that expands and engulfs the components destined for digestion during autophagy.

Autophagic flux

The whole process of autophagy, including autophagosome formation, maturation, fusion with lysosomes, subsequent breakdown and the release of macromolecules back into the cytosol.

Lipofuscin

A yellowish brown, autofluorescent, lipid-containing pigment that accumulates in the cytoplasm of cells during ageing.

Ischaemic preconditioning

(IPC). An endogenous adaptive mechanism elicited by brief ischaemia that protects against a subsequent more sustained ischaemic insult.

Chemical chaperones

Small molecules that enhance protein folding and/or stability.

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Tang, C., Livingston, M.J., Liu, Z. et al. Autophagy in kidney homeostasis and disease. Nat Rev Nephrol 16, 489–508 (2020). https://doi.org/10.1038/s41581-020-0309-2

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