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
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Basal autophagy is essential to the maintenance of kidney homeostasis, structure and function.
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Autophagy is suppressed in aged kidneys, which accelerates the progression of ageing and age-related kidney diseases.
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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.
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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.
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Autophagy defects in kidney cells of both tubular and glomerular compartments contribute to the development of diabetic kidney disease and focal segmental glomerulosclerosis.
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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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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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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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Glossary
- Vesicle nucleation
-
The process of mobilizing a small group of molecules to the phagophore assembly site to form a phagophore during autophagy.
- Phagophore
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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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DOI: https://doi.org/10.1038/s41581-020-0309-2
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