Deletion of PPAR-gamma in immune cells enhances susceptibility to antiglomerular basement membrane disease

Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been shown to be immunoregulatory in autoimmune diseases by inhibiting production of a number of inflammatory mediators. We investigated whether PPAR-gamma gene deletion in hematopoietic cells would alter disease pathogenesis in the antiglomerular basement membrane (anti-GBM) mouse model. PPAR-gamma(+/+) and PPAR-gamma(-/-)mice were immunized with rabbit antimouse GBM antibodies and lipopolysaccharide and evaluated for two weeks. Although both the PPAR-gamma(+/+) and PPAR-gamma(-/-)mice had IgG deposition in the glomerulus and showed proteinuria two weeks after injection, glomerular and tubulointerstitial disease in PPAR-gamma(-/-)mice were significantly more severe compared with the PPAR-gamma(+/+) animals. We observed that the PPAR-gamma(-/-)mice had decreased CD4(+) CD25(+) regulatory T cells and an increased CD8(+): CD4(+) ratio as compared with the PPAR-gamma(+/+) mice, suggesting that PPAR-. has a role in the regulation of T cells. Furthermore, plasma interleukin-6 levels were significantly increased in the PPAR-gamma(-/-)mice at two weeks as compared with the PPAR-gamma(+/+) animals. Taken together, these studies show that the lack of PPAR-gamma expression enhances inflammatory renal disease in the anti-GBM antibody-induced glomerulonephritis mouse model and suggests targeting PPAR-gamma may have therapeutic efficacy.