Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential

Abstract

Diabetic kidney disease, a leading cause of end-stage renal disease, has become a serious public health problem worldwide and lacks effective therapies. Autophagy is a highly conserved lysosomal degradation pathway that removes protein aggregates and damaged organelles to maintain cellular homeostasis. As important stress-responsive machinery, autophagy is involved in the pathogenesis of various diseases. Emerging evidence has suggested that dysregulated autophagy may contribute to both glomerular and tubulointerstitial pathologies in kidneys under diabetic conditions. This review summarizes the recent findings regarding the role of autophagy in the pathogenesis of diabetic kidney disease and highlights the regulation of autophagy by the nutrient-sensing pathways and intracellular stress signaling in this disease. The advances in our understanding of autophagy in diabetic kidney disease will facilitate the discovery of a new therapeutic target for the prevention and treatment of this life-threatening diabetes complication.

Keywords: AMPK; ER stress; Hypoxia; Reactive oxygen species; Sirt1; mTOR.

Fig. 1

Regulation of autophagy under non-diabetic and diabetic conditions. a Under non-diabetic conditions, the autophagic response in the kidney is normal and competent. Intracellular stresses such as hypoxia, ROS, and ER stress can induce autophagy. Nutrient depletion or low energy may also enhance autophagy by inhibiting mTORC1 and activating AMPK and SIRT1. Autophagy activation under non-diabetic conditions can maintain cellular homeostasis and protect against renal injury. b Under diabetic conditions, hyperglycemia activates mTORC1 and suppresses the activity of AMPK and SIRT1. Hyperactivated mTORC1 can inhibit autophagy by phosphorylating ULK1. The suppression of AMPK and SIRT1 further impairs autophagy under diabetic conditions. In early stage diabetes, hyperglycemia-induced intracellular stresses may activate autophagy as a compensatory response for cell protection. In late stage diabetes, however, sustained disturbance of the nutrient-sensing pathways overwhelmingly suppresses autophagy in the kidney, eventually leading to dysregulated autophagy and the progression of DKD. The solid lines in green with arrowheads represent stimulating effects. The sold lines in red with truncated end indicate inhibiting effects. The dotted lines stand for the regulatory effects that are disturbed and altered under diabetic conditions. AMPK AMP-activated protein kinase, ATF activating transcription factor, ATG autophagy-related, BNIP3 BCL2/adenovirus E1B 19-kDa interacting protein 3, CHOP C/EBP homologous protein, DEPTOR DEP domain-containing mTOR-interacting protein, DKD diabetic kidney disease, eIF2α eukaryotic initiation factor 2α, ER endoplasmic reticulum, FIP200 focal adhesion kinase family interacting protein of 200 kDa, FoxO3a forkhead box O3a, GβL G protein β-subunit-like protein, HIF1 hypoxia-inducible factor 1, IRE1 inositol requiring enzyme 1, JNK1 c-jun N-terminal kinase 1, LKB1 liver kinase B1, MAPLC3/LC3 microtubule-associated protein light chain 3, mTORC1 mechanistic target of rapamycin complex 1, PERK protein kinase RNA-like ER kinase, PRAS40 protein-rich Akt substrate of 40 kDa, PtdIns3K class III phosphatidylinositol 3 kinase, RAPTOR regulatory associated protein of mTOR, REDD1 regulated in development and DNA damage responses 1, Rheb Ras homolog enriched in brain, ROS reactive oxygen species, SIRT1 sirtuin 1, TSC1/2 tuberous sclerosis complex ½, ULK1/2 Unc-51-like ½, VPS vacuolar protein sorting