Prevention of Chronic Fatal Lupus Nephritis in NZM2328 Mice by Replacing the Chronic-Glomerulonephritis-Associated Cgnzl Locus and Identification of Candidate Cgnzl Genes

NZM2328 mice are a model for human systemic lupus erythematosus (SLE). In a previous linkage analysis using [(NZM2328 X C57L/J)F1 X NZM2328] mice, Cgnz1 and Agnz1 on distal chromosome (chr.) 1 were found to be linked to chronic glomerulonephritis (GN) and acute GN, respectively (1, 2). However, the Cgnz1 and Agnz1 genes have not yet been identified. To refine the Cgnz1 interval, a recombinant congenic strain NZM.Lc1R27 (R27) was generated and characterized. R27 mice have an 8Mb chr.1 fragment of C57L/J on a NZM2328 background, which replaces the Cgnz1 interval but not the Agnz1 interval of NZM2328. The development of autoantibodies and severe proteinuria are significantly suppressed in R27 female mice compared to NZM2328 female mice. Although 630f the R27 female mice develop acute GN, the progression to chronic GN is significantly inhibited in R27 females at 12 months of age. These observations support the hypotheses that 1) acute GN and chronic GN are under separate genetic control involving distinct mechanisms, and that 2) acute GN need not progress to chronic GN leading to end stage renal failure. By generating and characterizing a panel of Cgnz1-interval specific recombinant congenic strains, the Cgnz1 locus was refined to a 1.3Mb region containing 45 genes. Studies using real-time PCR and flow cytometry showed that the mRNA levels of Apoa2 and 1700009P17Rik were significantly higher in R27 kidneys than in NZM2328 kidneys, and that Ly108-1, Ly9, Cd84, and Slamf1 of the SLAM/CD2 family were significantly overexpressed in NZM2328 lymphocytes compared to R27 lymphocytes. The ii identification of these candidate Cgnz1 genes shows that both the immune compartment and the targeted end organ are involved in SLE pathogenesis. In summary, this dissertation shows that the development of chronic GN in NZM2328 mice is prevented by replacing the Cgnz1 locus of NZM2328 with that of C57L/J, and has identified several candidate Cgnz1 genes that may contribute to lupus nephritis. iii Dedication This dissertation is dedicated to my parents Guohua Geand Haizhen Yan, who are always loving and supportive to me.

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