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Agonist Pioglitazone Improves Cardiometabolic Risk and Renal Inflammation in Murine Lupus1
,
* Division of Rheumatology and
Division of Nephrology, Department of Internal Medicine; and
Department of Pathology, University of Michigan, Ann Arbor, MI 48109
Individuals with systemic lupus erythematosus (SLE) have a striking increase in the risk of premature atherosclerosis, a complication preceded by significant subclinical vascular damage. A proposed mechanism leading to accelerated vascular disease in SLE is an imbalance between vascular damage and repair, as patients with this disease display significant abnormalities in phenotype and function of endothelial progenitor cells. In addition, individuals with SLE have a higher incidence of insulin resistance which may further contribute to the increased cardiovascular risk. This study examined the role of the peroxisome proliferator activated receptor 
agonist pioglitazone in improving endothelial function, endothelial progenitor cell numbers and functional capacity, metabolic parameters, and disease activity in the lupus-prone murine model New Zealand Black/New Zealand White (NZB x NZW)F1. Ten-week-old prenephritic female NZB/NZW F1 mice were exposed to 10 or 25 mg/kg/day of oral pioglitazone or vehicle for 15 or 24 wk. Mice exposed to pioglitazone exhibited pronounced enhancement in endothelial-dependent vasorelaxation of thoracic aortas and in endothelial progenitor cell function, as assessed by the capacity of bone marrow-derived endothelial progenitor cells to differentiate into mature endothelial cells. Pioglitazone-treated mice showed improvement in insulin resistance, adipokine, and lipid profile. Kidneys from pioglitazone-treated mice showed significant decreases in immune complex deposition, renal inflammation, T cell glomerular infiltration, and intrarenal synthesis of TNF-
, IL-1β, and VCAM-1. These results indicate that peroxisome proliferator-activated receptor agonists could serve as important tools in the prevention of premature cardiovascular disease and organ damage in SLE.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by the Alliance for Lupus Research and the Anthony S. Gramer Fund in Inflammation Research (both to M.J.K.). M.K. was funded by a Target Identification Award by the Alliance for Lupus Research and by National Institutes of Health Grant P30 DK081943. The study was also funded in part by National Institutes of Health through the University of Michigan’s Cancer Center Support Grant (P30 CA46592) and Rheumatic Disease Core Center Grant (P30 AR48310).
2 Address correspondence and reprint requests to Dr. Mariana J. Kaplan, Division of Rheumatology, University of Michigan Medical School, 1150 West Medical Center Drive, 5520 Medical Science Research Building I, Ann Arbor, MI 48109-5680. Email address: makaplan{at}umich.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; PPAR-, peroxisome proliferator-activated receptor ; CV, cardiovascular; TZD, thiazolidinedione; EPC, endothelial progenitor cell; PE, phenylephrine; Ach, acetylcholine; SNP, sodium nitroprusside; diI, 1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; ac-LDL, acetylated low density protein; LDL, low density lipoprotein; HDL, high density lipoprotein; BUN, blood urea nitrogen.
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