Journal Article

Lipophagy deficiency exacerbates ectopic lipid accumulation and tubular cells injury in diabetic nephropathy

Han, Yachun, Xiong, Xiaofen, Xiao, Ying, Xiong, Shan, Jiang, Na, Wei, Ling, Zhu, Xuejing, Gao, Peng, Sun, Lin, Yang, Shikun, Yang, Ming, Zhao, Hao

2021

Overview

Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13 / 13/1 / 13/51 / 14/19 / 14/28 / 64/60 / 692/163/2743/137/138 / 692/699/1585/104 / 96/2 / Adiponectin / Adult / AMP-Activated Protein Kinases - metabolism / Animals / Antibodies / Apoptosis / Apoptosis - drug effects / Autophagosomes - drug effects / Autophagosomes - metabolism / Autophagy / Autophagy - drug effects / Autophagy-Related Protein-1 Homolog - antagonists & inhibitors / Autophagy-Related Protein-1 Homolog - metabolism / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Culture / Cell Line / Chloroquine / Diabetes / Diabetes mellitus / Diabetic Nephropathies - pathology / Diabetic nephropathy / Enzyme Activators - pharmacology / Female / Fibrosis / Gene Ontology / Glucose - toxicity / Humans / Immunology / Intracellular Signaling Peptides and Proteins - antagonists & inhibitors / Intracellular Signaling Peptides and Proteins - metabolism / Kidney Tubules - drug effects / Kidney Tubules - pathology / Kidney Tubules - physiopathology / Kidneys / Life Sciences / Lipid Droplets - ultrastructure / Lipid Metabolism - drug effects / Lipids / Male / Mice / Mice, Inbred C57BL / Microtubule-Associated Proteins - metabolism / Middle Aged / Nephropathy / Oxidative Stress - drug effects / Phagocytosis / Phosphorylation - drug effects / Piperidines - pharmacology / rab7 GTP-Binding Proteins - metabolism / Receptors, Adiponectin - genetics / Receptors, Adiponectin - metabolism