title: Absence of the lysosomal protein Limp-2 attenuates renal injury in crescentic glomerulonephritis.
abstract: In humans, mutations of the intrinsic lysosomal protein SCARB2 are associated with myoclonic epilepsy, collapsing focal and segmental glomerulosclerosis, and tubular proteinuria. Mice with deficiency of Limp-2 (the murine homologue) develop tubular proteinuria but not focal and segmental glomerulosclerosis and they have a defect in macrophage function. To further elucidate the role of Limp-2 in immune function, we induced anti-glomerular basement membrane (GBM) model of crescentic glomerulonephritis in wild-type (WT) and Limp-2(-/-) littermates by intraperitoneal injections of nephrotoxic sheep serum. Renal injury and immune responses were assessed on day 14. Compared with WT, Limp-2(-/-) mice had significantly reduced crescent formation, interstitial inflammation and a trend to reduced tubulointerstitial injury. On day 1 during the heterologous phase of the disease, albuminuria was significantly increased in WT but not in Limp-2(-/-) mice. On day 14, albuminuria and renal function were similar in the two groups. There was, however, a significant reduction in the influx of glomerular macrophages and CD4(+) T cells in Limp-2(-/-) mice. Interleukin (IL)-4 and macrophage chemoattractant protein-1 (MCP-1) mRNA expression levels were significantly reduced. Despite the reduction in numbers of infiltrating cells, flow cytometry showed no difference in macrophage or T-cell numbers in the peripheral blood from untreated mice. The systemic humoral immune response, determined by glomerular mouse immunoglobulin G (IgG) deposition and mouse anti-sheep IgG subclass production, was similar in both groups. These data suggest that absence of Limp-2 reduces inflammation in experimental crescentic glomerulonephritis with decreased macrophage and T-cell infiltration in the kidney. It suggests an important role for Limp-2 in mediating the inflammatory response.
authors.affiliation: 1] Department of Nephrology, Austin Health, Melbourne, Victoria, Australia [2] Department of Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia [3] Department of Renal Medicine, Faculty of Medicine, Nursing and Health Sciences, Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.
authors.forename: Darren Hiu Kwong
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Monash Medical Centre, Centre of Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia.
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.affiliation: The Institute for Breathing and Sleep, Austin Health, Melbourne, Victoria, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Katerelos
authors.affiliation: The Institute for Breathing and Sleep, Austin Health, Melbourne, Victoria, Australia.
authors.forename: Scott Andrew
authors.initials: SA
authors.lastname: Fraser
authors.affiliation: The Institute for Breathing and Sleep, Austin Health, Melbourne, Victoria, Australia.
authors.forename: Kurt
authors.initials: K
authors.lastname: Gleich
authors.affiliation: Department of Medicine, Monash Medical Centre, Centre of Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia.
authors.forename: Stephen Roger
authors.initials: SR
authors.lastname: Holdsworth
authors.affiliation: 1] Department of Nephrology, Austin Health, Melbourne, Victoria, Australia [2] Department of Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia [3] The Institute for Breathing and Sleep, Austin Health, Melbourne, Victoria, Australia.
authors.forename: David Anthony
authors.initials: DA
authors.lastname: Power
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D018955:CD36 Antigens / Q000172:deficiency*; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000172:deficiency*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D018955:CD36 Antigens; D051907:Lysosomal Membrane Proteins; C489452:Scarb2 protein, mouse