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J Am Soc Nephrol. 2015 Jun;26(6):1402-13. doi: 10.1681/ASN.2014050508. Epub 2014 Sep 30.

Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis.

Author information

1
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.
2
Departments of Drug Discovery and Biomedical Sciences and.
3
Department of Medicine, Division of Rheumatology and Immunology and.
4
Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York;
5
Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina;
6
Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York; Research Service, Northport Veterans Affairs Medical Center, Northport, New York; and.
7
Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; Department of Medicine, Division of Rheumatology and Immunology and.
8
Department of Pharmacology and Toxicology and the James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky Nowling@musc.edu leah.siskind@louisville.edu.

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.

KEYWORDS:

chronic GN; glomerular disease; immune complexes; lipids; lupus nephritis

PMID:
25270066
PMCID:
PMC4446878
DOI:
10.1681/ASN.2014050508
[Indexed for MEDLINE]
Free PMC Article

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