ROLE OF PPAR GAMMA IN LUPUS NEPHRITIS

Summary

Principal Investigator: G Gilkeson
Abstract: DESCRIPTION: (Adapted from the Investigator's abstract): Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by immune complex glomerulonephritis and infiltration of activated macrophages into the glomerulus. In the MRL/lpr mouse model of lupus, macrophages and mesangial cells are hyperresponsive to immune stimuli as evidenced by increased production of NO and TNF alpha compared to controls. Once activated by immune stimuli, macrophages and resident glomerular mesangial cells continue to secrete inflammatory mediators that maintain and enhance the local inflammatory state. Activators of the nuclear receptor PPAR gamma inhibit macrophage and mesangial cell activation. Our preliminary studies indicate that PPAR gamma expression is decreased in mesangial cells from MRL/lpr mice compared to controls. Furthermore, production of PG1J2, an intrinsic ligand for PPAR gamma, by MRL/lpr mesangial cells is significantly less than BALBIc mesangial cells. Our central hypothesis is that both at baseline and with immune stimulation there is a decrease in PPAR gamma expression and/or signaling in mesangial cells of MRL/lpr mice. Alterations in the PPAR gamma pathway result in a heightened and prolonged inflammatory response in MRL/lpr mice. To test this hypothesis the following specific aims are proposed: 1. Determine the levels of PPAR gamma protein, mRNA and regulation of its expression in mesangial cells obtained from MRL/lpr, MRL+/+, NZB/NZW, BALB/c, B6/lpr and B6 mice. 2. Determine the concentration-response dependent effects of PGJ2 and pioglitazone, a PPAR gamma agonist, on the synthesis and/or induction of NO/NOS2, TNF alpha, COX-1 and COX-2 and apoptosis, proliferation and matrix protein production in mesangial cells of MRL/Ipr, MRL+/+, NZB/NZW, BALB/c, B6/lpr and B6 mice stimulated with LPS/IFN gamma, IL-1 beta or TNF alpha. 3. Determine the time course of synthesis for PGJ2, PGD2, PGE2, PGI2, and TXA2 by mesangial cells from MRL/lpr, NZBINZW, BALB/c, B6/lpr and B6 mice and which COX is responsible for their synthesis. The effect of pioglitazone on their production will be determined. 4. Determine the effects of pioglitazone on the urinary excretion of NOx, protein, parent eicosanoids and metabolites, serum 3NT, GFR, renal, joint, and lung histology, and serum autoantibodies in MRL/lpr mice. To test these specific aims a combination of cell culture, molecular and cellular biology and in vivo animal studies will be performed. These studies will provide important insight into the role of PPAR gamma and its ligands in controlling the inflammatory response in lupus nephritis. We and others have shown that the inflammatory response in lupus nephritis can be blocked, decreasing proteinuria and pathologic renal disease, without affecting immune complex deposition. As agonists of PPAR gamma (the thiazolidinediones) are already approved for human use, insight gained from these studies can be quickly translated into human trials.
Funding Period: 2001-03-01 - 2006-11-30
more information: NIH RePORT

Top Publications

  1. pmc NADPH oxidase and nitric oxide synthase-dependent superoxide production is increased in proliferative lupus nephritis
    J C Oates
    1Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, USA
    Lupus 22:1361-70. 2013
  2. ncbi Peroxisome proliferation-activated receptor (PPAR)gamma is not necessary for synthetic PPARgamma agonist inhibition of inducible nitric-oxide synthase and nitric oxide
    Michelle B Crosby
    Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
    J Pharmacol Exp Ther 312:69-76. 2005
  3. ncbi A novel PPAR response element in the murine iNOS promoter
    Michelle B Crosby
    Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathon Lucas Street, Ste 912 CSB, Charleston, SC 29425, USA
    Mol Immunol 42:1303-10. 2005
  4. ncbi Inflammatory modulation of PPAR gamma expression and activity
    Michelle B Crosby
    Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
    Clin Immunol 118:276-83. 2006
  5. ncbi Regulation of Fli1 gene expression and lupus
    Tamara K Nowling
    Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street, Ste 912 CSB, Charleston, SC 29425, United States
    Autoimmun Rev 5:377-82. 2006
  6. pmc Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes
    Tamara K Nowling
    Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street, Ste 912 CSB, Charleston, SC 29425, USA
    Mol Immunol 45:1-12. 2008

Scientific Experts

  • Tamara K Nowling
  • Michelle B Crosby
  • J C Oates
  • Gary S Gilkeson
  • Christopher J Nicol
  • John Zhang
  • John L Svenson
  • Frank J Gonzalez
  • S R Shaftman
  • G S Gilkeson
  • A K Mashmoushi
  • John Svenson

Detail Information

Publications6

  1. pmc NADPH oxidase and nitric oxide synthase-dependent superoxide production is increased in proliferative lupus nephritis
    J C Oates
    1Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, USA
    Lupus 22:1361-70. 2013
    ..We hypothesized that markers of SO production would be increased in active PLN and that SO production would be dependent on the activity of select enzymes in the renal cortex...
  2. ncbi Peroxisome proliferation-activated receptor (PPAR)gamma is not necessary for synthetic PPARgamma agonist inhibition of inducible nitric-oxide synthase and nitric oxide
    Michelle B Crosby
    Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
    J Pharmacol Exp Ther 312:69-76. 2005
    ..Intrinsic PPARgamma function, in the absence of synthetic agonists, however, may play a role in inflammatory modulation...
  3. ncbi A novel PPAR response element in the murine iNOS promoter
    Michelle B Crosby
    Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathon Lucas Street, Ste 912 CSB, Charleston, SC 29425, USA
    Mol Immunol 42:1303-10. 2005
    ..The PPRE is not necessary, however, for synthetic PPARgamma agonists to inhibit iNOS expression...
  4. ncbi Inflammatory modulation of PPAR gamma expression and activity
    Michelle B Crosby
    Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
    Clin Immunol 118:276-83. 2006
    ..This activity was restored with the addition of a NOS enzyme inhibitor. These results indicate that the activation of inflammatory pathways may lead to reduced activity and expression of PPARgamma, further exacerbating the disease state...
  5. ncbi Regulation of Fli1 gene expression and lupus
    Tamara K Nowling
    Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street, Ste 912 CSB, Charleston, SC 29425, United States
    Autoimmun Rev 5:377-82. 2006
    ..Identifying upstream regulators of Fli1 in lymphocytes will be critical for understanding lymphocyte development and the consequences of dysregulation and may be of value in developing future treatments for lupus...
  6. pmc Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes
    Tamara K Nowling
    Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 96 Jonathan Lucas Street, Ste 912 CSB, Charleston, SC 29425, USA
    Mol Immunol 45:1-12. 2008
    ..Furthermore, the presence of a polymorphic microsatellite in the Fli1 promoter may contribute to increased Fli1 expression in T cells during lupus disease progression...