Immunoglobulin locus associates with serum IgG levels and albuminuria

The interaction between IgG and Fc-γ receptors in glomeruli contributes to the development of several types of proteinuric glomerular disease, but the involvement of immunological mechanisms in hypertensive renal injury is incompletely understood. Here, we investigated serum IgG levels in SHR-A3 rats, which develop hypertensive injury, and compared them with the injury-resistant SHR-B2 line. At 18 weeks old, SHR-A3 rats had serum total IgG levels nearly twice those of SHR-B2 rats, although subclass IgG2b was undetectable in SHR-A3 rats compared with mean levels (± SEM) of 80.7 ± 12.8 mg/dl (18 weeks) and 116.6 ± 19.0 mg/dl (30 weeks) in SHR-B2 rats. In addition, these two strains had significantly different serum levels of IgG1, IgG2a, and IgG2c; differences persisted at 30 weeks for all subclasses except IgG2a. Genetic mapping revealed that a locus on chromosome 6 linked to IgG subclass levels that affected IgG1, IgG2b, and IgG2c but not IgG2a. The mapped haplotype block contains IgH, suggesting regulation of three of four serum IgG subclass levels in cis. Resequencing revealed variation in the sequence of the Fc portion of the IgG heavy chain, which predicts important functional changes. To examine whether there is any relationship between this haplotype block and susceptibility to renal injury, we examined the effect of SHR-A3 and SHR-B2 alleles at this block on albumin excretion in an F2 intercross. Albuminuria doubled with inheritance of SHR-A3 alleles. In summary, allelic variation in IgH or nearby genes may modulate the susceptibility to hypertensive renal injury in SHR-A3 rats.