Inflammatory modulation of PPAR gamma expression and activity.
Nitric oxide (NO) production increases with age in the lupus-prone MRL/lpr mouse, paralleling disease activity. One mechanism for excess NO production in MRL/lpr mice may be a defect in down-regulatory mechanisms of the iNOS pathway. A potential modulator of NO is the nuclear hormone receptor peroxisome proliferation activated receptor gamma (PPARgamma). We demonstrate that renal PPARgamma protein expression was altered as disease progressed in MRL/lpr mice, which paralleled increased iNOS protein expression. Additionally, MRL/lpr-derived primary mesangial cells expressed less PPARgamma than BALB/c mesangial cells and produced more NO in response to LPS and IFNgamma. Furthermore, PPARgamma activity was reduced in mesangial cells following exposure to inflammatory mediators. 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.
Crosby
Michelle B
MB
Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Zhang
John
J
Nowling
Tamara M
TM
Svenson
John L
JL
Nicol
Christopher J
CJ
Gonzalez
Frank J
FJ
Gilkeson
Gary S
GS
D000367:Age Factors; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005260:Female; D018836:Inflammation Mediators / Q000502:physiology*; D007668:Kidney / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D047495:PPAR gamma / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D018836:Inflammation Mediators; D047495:PPAR gamma; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse