title: Autophagy-Lysosome Pathway in Renal Tubular Epithelial Cells Is Disrupted by Advanced Glycation End Products in Diabetic Nephropathy.
abstract: It has been suggested that autophagy protects renal tubular epithelial cells (TECs) from injury in diabetic nephropathy (DN). However, the manner in which the autophagy-lysosome pathway is changed in this state remains unclear. In this study of DN, we investigated the autophagic activity and lysosomal alterations in vivo and in vitro. We found that autophagic vacuoles and SQSTM1-positive proteins accumulated in TECs from patients with DN and in human renal tubular epithelial cell line (HK-2 cells) treated with advanced glycation end products (AGEs), the important factors that involved in the pathogenesis of DN. In HK-2 cells, exposure to AGEs caused a significant increase in autophagosomes but a marked decrease in autolysosomes, and the lysosomal turnover of LC3-II was not observed, although LC3-II puncta were co-localized with the irregular lysosomal-associated membrane protein1 granules after AGEs treatment. Furthermore, lysosomal membrane permeabilization was triggered by AGEs, which likely resulted in a decrease in the enzymatic activities of cathepsin B and cathepsin L, the defective acidification of lysosomes, and suppression of the lysosomal degradation of DQ-ovalbumin. Oxidative stress evoked by AGEs-receptor for AGE interaction likely played an important role in the lysosomal dysfunction. Additionally, ubiquitinated proteins were co-localized with SQSTM1-positive puncta and accumulated in HK-2 cells after exposure to AGEs, indicating blocked degradation of SQSTM1-positive and ubiquitinated aggregates. Taken together, the results show that lysosomal membrane permeabilization and lysosomal dysfunction are triggered by AGEs, which induce autophagic inactivation in TECs from patients with DN. Disruption of the autophagy-lysosome pathway should be focused when studying the mechanisms underlying DN.
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Wei Jing
authors.initials: WJ
authors.lastname: Liu
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Shen
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Rui Hong
authors.initials: RH
authors.lastname: Chen
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Hong-Luan
authors.initials: HL
authors.lastname: Wu
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Yan Jin
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Jian Kun
authors.initials: JK
authors.lastname: Deng
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Qiu Hua
authors.initials: QH
authors.lastname: Chen
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Pan
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Chang-mei
authors.initials: CM
authors.lastname: Huang Fu
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Jing-li
authors.initials: JL
authors.lastname: Tao
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liang
authors.affiliation: From the Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong 524001, China hf-liu@263.net.
authors.forename: Hua-feng
authors.initials: HF
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy; D002463:Cell Membrane Permeability; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D017127:Glycation End Products, Advanced
keywords: autophagy; diabetic nephropathy; lysosome; reactive oxygen species (ROS); receptor for advanced glycation end products (RAGE)