title: Podocyte injury-driven lipid peroxidation accelerates the infiltration of glomerular foam cells in focal segmental glomerulosclerosis.
abstract: Intracapillary foam cell infiltration with podocyte alterations is a characteristic pathology of focal segmental glomerulosclerosis (FSGS). We investigated the possible role of podocyte injury in glomerular macrophage and foam cell infiltration in a podocyte-selective injury model (NEP25 mice) and hypercholesterolemic model [low-density lipoprotein receptor deficiency (LDLR(-/-)) mice] with doxorubicin-induced nephropathy. Acute podocyte selective injury alone failed to induce glomerular macrophages in the NEP25 mice. However, in the doxorubicin-treated hypercholesterolemic LDLR(-/-) mice, glomerular macrophages/foam cells significantly increased and were accompanied by lipid deposition and the formation and ingestion of oxidized phospholipids (oxPLs). Glomerular macrophages significantly correlated with the amount of glomerular oxPL. The NEP25/LDLR(-/-) mice exhibited severe hypercholesterolemia, glomerular lipid deposition, and renal dysfunction. Imaging mass spectrometry revealed that a major component of oxidized low-density lipoprotein, lysophosphatidylcholine 16:0 and 18:0, was present only in the glomeruli of NEP25/LDLR(-/-) mice. Lysophosphatidylcholine 16:0 stimulated mesangial cells and macrophages, and lysophosphatidylcholine 18:0 stimulated glomerular endothelial cells to express adhesion molecules and chemokines, promoting macrophage adhesion and migration in vitro. In human FSGS, glomerular macrophage-derived foam cells contained oxPLs accompanied by the expression of chemokines in the tuft. In conclusion, glomerular lipid modification represents a novel pathology by podocyte injury, promoting FSGS. Podocyte injury-driven lysophosphatidylcholine de novo accelerated glomerular macrophage-derived foam cell infiltration via lysophosphatidylcholine-mediated expression of adhesion molecules and chemokines in glomerular resident cells.
authors.affiliation: Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Division of Rheumatology, Department of Internal Medicine, Kanazawa Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hara
authors.affiliation: Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Manabe
authors.affiliation: Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Takashima
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Juri
authors.initials: J
authors.lastname: Hamada
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.affiliation: Department of Internal Medicine, Institute of Medical Science, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: nagatam@md.tsukuba.ac.jp.
authors.forename: Michio
authors.initials: M
authors.lastname: Nagata
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D015227:Lipid Peroxidation / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
chemical_list: D011973:Receptors, LDL