Autophagy in kidney homeostasis and disease

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. In this Review, the authors summarize the basics of autophagy and the signalling pathways involved in its regulation, and examine the multiple roles of autophagy in kidney cells, from its involvement in kidney maintenance and responses to injury, to its potential contribution to glomerular and tubulointerstitial disease. 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 glomerulosc