Fig. 2.
An overview of the regulation of autophagy by extracellular and intracellular stresses in the pathogenesis of diabetic nephropathy (DN). Three major nutrient-sensing signal pathways modulate autophagy activity under diabetic conditions through activation of mTORC1 and inhibition of AMPK and SIRT1 to negatively regulate autophagy activity. AMPK and mTORC1 oppositely regulate the Ulk1/2-Atg13-FIP200 complex. AMPK directly activates Ulk1/2 to induce autophagy. SIRT1 interacts with essential components of the autophagy machinery, such as Atg5, Atg7, and LC3, and the transcription factor FoxO3 to induce autophagy. Diabetes also induces alterations of intracellular metabolism such as accumulation of intracellular advanced glycation end-products (AGEs) and extracellular AGEs that act via their interaction with receptor for AGEs (RAGE). Other cellular events include increased reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, enhanced protein kinase C (PKC) activity and increased flux through polyol pathways, hypoxia, and activation of the renin angiotensin system (RAS), which modulate autophagic activity and contribute to the development of DN. Impairment of autophagy activity lead to cellular injury responses including apoptosis, inflammation, and ECM accumulation, resulting in progression of DN with development of albuminuria, decline in GFR, and renal fibrosis.
Abbreviations: mTORC1, mechanistic target of rapamycin complex 1; AMPK, adenosine monophosphate-activated protein kinase (AMPK); SIRT1, silent information regulator T1; Ulk1/2, Unc-51-like kinase 1/2; Atg, autophagy-related gene; LC3, microtubule-associated protein 1 light chain 3; FoxO3, forkhead box O3; ECM, extracellular matrix; GFR, glomerular filtration rate.