title: ATP synthase subunit-β down-regulation aggravates diabetic nephropathy.
abstract: In this study, we investigated the role of ATP synthase subunit-β (ATP5b) in diabetic nephropathy. Histopathological changes, fibrosis, and protein expressions of α-smooth muscle actin (α-SMA), advanced glycation end-products (AGEs), and ATP5b were obviously observed in the kidneys of db/db diabetic mice as compared with the control db/m(+) mice. The increased ATP5b expression was majorly observed in diabetic renal tubules and was notably observed to locate in cytoplasm of tubule cells, but no significant increase of ATP5b in diabetic glomeruli. AGEs significantly increased protein expression of ATP5b and fibrotic factors and decreased ATP content in cultured renal tubular cells via an AGEs-receptor for AGEs (RAGE) axis pathway. Oxidative stress was also induced in diabetic kidneys and AGEs-treated renal tubular cells. The increase of ATP5b and CTGF protein expression in AGEs-treated renal tubular cells was reversed by antioxidant N-acetylcysteine. ATP5b-siRNA transfection augmented the increased protein expression of α-SMA and CTGF and CTGF promoter activity in AGEs-treated renal tubular cells. The in vivo ATP5b-siRNA delivery significantly enhanced renal fibrosis and serum creatinine in db/db mice with ATP5b down-regulation. These findings suggest that increased ATP5b plays an important adaptive or protective role in decreasing the rate of AGEs-induced renal fibrosis during diabetic condition.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Nuclear Energy Research, Atomic Energy Council, Executive Yuan, Taoyuan, Taiwan.
authors.forename: Siao-Syun
authors.initials: SS
authors.lastname: Guan
authors.affiliation: Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Tien
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Departments of Integrated Diagnostics &Therapeutics and Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine
chemical_list: D017127:Glycation End Products, Advanced; D021122:Protein Subunits; D055513:Connective Tissue Growth Factor; C530489:ATP5b protein, mouse; D025261:Mitochondrial Proton-Translocating ATPases