title: Fatty Acid-Binding Protein 4 mediates apoptosis via endoplasmic reticulum stress in mesangial cells of diabetic nephropathy.
abstract: Type 2 diabetes is characterized by hyperglycemia and deregulated lipid metabolism with increased plasma non-esterified fatty acids (NEFA). Apoptosis of glomerular cells is a hallmark in diabetic glomerulosclerosis. Fatty acid-binding protein 4 (FABP4), a carrier protein for fatty acids, has been linked to diabetes and diabetic nephropathy (DN). Here we aimed to investigate the link between FABP4 and apoptosis in diabetic glomerulosclerosis. We first evaluated the presence of FABP4 and ER stress markers as well as apoptosis-related proteins in renal biopsies of patients with DN. Then we used FABP4 inhibitor BMS309403 or siRNA to further investigate the role of FABP4 in ER stress and apoptosis induced by NEFA or high glucose in cultured human mesangial cells (HMCs). We found FABP4 was expressed mainly in glomerular mesangial cells of the human renal biopsies and the glomerular FABP4 was increased in renal biopsies of DN. The up-regulation of FABP4 was accompanied with increased glucose-regulated protein 78 (GRP78) and Caspase-12 as well as down-regulated B-cell CLL/lymphoma 2 (Bcl-2) in glomeruli. Along with the induction of FABP4 and apoptosis, GRP78 and its three sensors as well as C/EBP homologous protein (CHOP) and Caspase-12 were induced in HMCs treated with NEFA or high glucose and these responses were attenuated or even abrogated by treating with FABP4 inhibitor or FABP4 siRNA. Ultrastructure observation confirmed the lipotoxicity of oleic acid by showing the morphological damage in HMCs. Our data suggest that FABP4 in glomerular mesangial cells is up-regulated in DN and FABP4 mediates apoptosis via the ER stress in HMCs.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Pathology, the First Hospital of Changsha City, Changsha, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Health and Sport Science, Graduates School of Health Sciences, Matsumoto University, Matsumoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ehara
authors.affiliation: Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, China. Electronic address: lianshanzh@163.com.
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering; D015854:Up-Regulation
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D001713:Biphenyl Compounds; D000091342:Endoplasmic Reticulum Chaperone BiP; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; C000717247:HSPA5 protein, human; D011720:Pyrazoles; D034741:RNA, Small Interfering; D005947:Glucose
keywords: Apoptosis; Diabetic nephropathy; Endoplasmic reticulum stress; Fatty acid-binding protein 4; Mesangial cell