Kidney Week

Abstract: TH-PO419

Knockdown of Ugcg Induces Kidney Autoimmune Disease

Session Information

• Nutrition, Inflammation, Metabolism: Basic Mechanisms
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Nutrition, Inflammation, and Metabolism

• 1401 Nutrition, Inflammation, Metabolism

Authors

• Dupre, Tess, University of Louisville, Louisville, Kentucky, United States

Tess Dupre,

• Sharp, Cierra, University of Louisville, Louisville, Kentucky, United States

Cierra Sharp,

• Doll, Mark A., University of Louisville, Louisville, Kentucky, United States

Mark A. Doll,

• Sun, Ying, Cincinnati Children''s Hospital, Cincinnati, Ohio, United States

Ying Sun,

• Megyesi, Judit, University of Arkansas for Medical Science, Little Rock, Arkansas, United States

Judit Megyesi,

• Beverly, Levi J., University Of Louisville, Louisville, Kentucky, United States

Levi J. Beverly,

• Nowling, Tamara, Medical University of South Carolina, Charleston, South Carolina, United States

Tamara Nowling,

• Davis, Deanna L, Virginia Commonwealth University, Richmond, Virginia, United States

Deanna L Davis,

• Siskind, Leah J., University of Louisville, Louisville, Kentucky, United States

Leah J. Siskind,

• Drake, Richard R, Medical University of South Carolina, Charleston, South Carolina, United States

Richard R Drake,

• Zhang, Wujuan, CCHMC, Cincinnati, Ohio, United States

Wujuan Zhang,

Background

Glycosphingolipids (GSLs) play a role in autoimmune kidney diseases, including lupus nephritis. Autoimmune kidney diseases are associated with chronic inflammation and recruitment of immune cells into the kidney. N-glycans play a role in regulating inflammatory pathways in autoimmune diseases. Importantly, data in the literature suggest interplay between GSL and N-glycan biosynthetic pathways that may be important in regulating inflammatory responses.

Methods

We generated transgenic mice containing an inducible shRNA that targets expression of Ugcg (Tet-O-shUgcg). Ugcg is the gene that encodes for glucosylceramide synthase, the enzyme that catalyzes synthesis of glucosylceramide from ceramide. Tet-O-shUgcg mice were bred with CAG^+/-rtTA3 mice (CAG-rtTA3-Tet-O-shUgcg) for universal expression of the shRNA in the presence of doxycyline.

Results

Following Ugcg knockdown (KD), organized accumulations of CD19⁺ B cells and CD3⁺ T cells formed in the kidneys, which are defining features of tertiary lymphoid organs (TLOs). TLOs are ectopic accumulations of lymphoid cells that can arise in areas of chronic inflammation via lymphoid neogenesis. Data indicate that knockdown of Ugcg in kidney results in significant increases in levels of biantennary N-glycans relative to control, and decreases in branched multi-fucosylated glycans normally present in control kidneys. KD of Ugcg increases serum levels of total IgG and IgA.

Conclusion

KD of Ugcg alters N-glycan signatures in the kidney, induces TLO formation, and autoimmunity. This transgenic mouse model is novel tool for studying the role of GSLs and N-glycans in kidney inflammation and autoimmunity and may represent a new mouse model of autoimmune kidney disease.

Funding

• NIDDK Support