WY14,643, a PPARalpha ligand, attenuates expression of anti-glomerular basement membrane disease.
Peroxisome proliferator-activated receptor alpha (PPARalpha) ligands are medications used to treat hyperlipidaemia and atherosclerosis. Increasing evidence suggests that these agents are immunosuppressive. In the following studies we demonstrate that WY14,643, a PPARalpha ligand, attenuates expression of anti-glomerular basement membrane disease (AGBMD). C57BL/6 mice were fed 0.05% WY14,643 or control food and immunized with the non-collagenous domain of the alpha3 chain of Type IV collagen [alpha3(IV) NC1] in complete Freund's adjuvant (CFA). WY14,643 reduced proteinuria and greatly improved glomerular and tubulo-interstitial lesions. However, the PPARalpha ligand did not alter the extent of IgG-binding to the GBM. Immunohistochemical studies revealed that the prominent tubulo-interstitial infiltrates in the control-fed mice consisted predominately of F4/80(+) macrophages and WY14,643-feeding decreased significantly the number of renal macrophages. The synthetic PPARalpha ligand also reduced significantly expression of the chemokine, monocyte chemoattractant protein (MCP)-1/CCL2. Sera from mice immunized with AGBMD were also evaluated for antigen-specific IgGs. There was a significant increase in the IgG1 : IgG2c ratio and a decline in the intrarenal and splenocyte interferon (IFN)-gamma mRNA expression in the WY14,643-fed mice, suggesting that the PPARalpha ligand could skew the immune response to a less inflammatory T helper 2-type of response. These studies suggest that PPARalpha ligands may be a novel treatment for inflammatory renal disease.
Archer
D C
DC
Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, CA, USA.
Frkanec
J T
JT
Cromwell
J
J
Clopton
P
P
Cunard
R
R
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D050533:Glomerular Basement Membrane / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000276:immunology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D020025:Peroxisome Proliferators / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D013154:Spleen / Q000276:immunology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D008024:Ligands; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; C006253:pirinixic acid