title: Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis.
abstract: Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.
authors.affiliation: Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; Department of Medicine, Division of Rheumatology and Immunology and Nowling@musc.edu leah.siskind@louisville.edu.
authors.forename: Tamara K
authors.initials: TK
authors.lastname: Nowling
authors.affiliation: Departments of Drug Discovery and Biomedical Sciences and.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Mather
authors.affiliation: Department of Medicine, Division of Rheumatology and Immunology and.
authors.forename: Thirumagal
authors.initials: T
authors.lastname: Thiyagarajan
authors.affiliation: Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York;
authors.forename: María José
authors.initials: MJ
authors.lastname: Hernández-Corbacho
authors.affiliation: Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Powers
authors.affiliation: Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: E Ellen
authors.initials: EE
authors.lastname: Jones
authors.affiliation: Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York; Research Service, Northport Veterans Affairs Medical Center, Northport, New York; and.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Snider
authors.affiliation: Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; Department of Medicine, Division of Rheumatology and Immunology and.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Oates
authors.affiliation: Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Richard R
authors.initials: RR
authors.lastname: Drake
authors.affiliation: Department of Pharmacology and Toxicology and the James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky Nowling@musc.edu leah.siskind@louisville.edu.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Siskind
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D018450:Disease Progression; D005500:Follow-Up Studies; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D008181:Lupus Nephritis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D016482:Urinalysis
chemical_list: D015415:Biomarkers; D006028:Glycosphingolipids; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C110128:Neu1 protein, mouse; D009439:Neuraminidase
keywords: chronic GN; glomerular disease; immune complexes; lipids; lupus nephritis