title: Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis.
abstract: Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetic patients have increased plasma concentrations of apolipoprotein C-I (apoCI), and meta-analyses found that a polymorphism in APOC1 is associated with an increased risk of developing nephropathy. To investigate whether overexpressing apoCI contributes to the development of kidney damage, we studied renal tissue and peritoneal macrophages from APOC1 transgenic (APOC1-tg) mice and wild-type littermates. In addition, we examined renal material from autopsied diabetic patients with and without diabetic nephropathy and from autopsied control subjects. We found that APOC1-tg mice, but not wild-type mice, develop albuminuria, renal dysfunction, and glomerulosclerosis with increased numbers of glomerular M1 macrophages. Moreover, compared to wild-type macrophages, stimulated macrophages isolated from APOC1-tg mice have increased cytokine expression, including TNF-alpha and TGF-beta, both of which are known to increase the production of extracellular matrix proteins in mesangial cells. These results suggest that APOC1 expression induces glomerulosclerosis, potentially by increasing the cytokine response in macrophages. Furthermore, we detected apoCI in the kidneys of diabetic patients, but not in control kidneys. Moreover, patients with diabetic nephropathy have significantly more apoCI present in glomeruli compared to diabetic patients without nephropathy, suggesting that apoCI could be involved in the development of diabetic nephropathy. ApoCI co-localized with macrophages. Therefore, apoCI is a promising new therapeutic target for patients at risk of developing nephropathy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bus
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Louise
authors.initials: L
authors.lastname: Pierneef
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Bor
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Wolterbeek
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: van Es
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Patrick Cn
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Bruijn
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jimmy F
authors.initials: JF
authors.lastname: Berbée
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000209:etiology / Q000473:pathology; D000818:Animals; D053302:Apolipoprotein C-I / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D053302:Apolipoprotein C-I; D016207:Cytokines
keywords: apolipoprotein CI; diabetes; glomerulopathy; inflammation; macrophages