Inflammatory modulation of PPARγ expression and activity

Nitric oxide (NO) production increases with age in the lupus-prone MRL/Ipr mouse, paralleling disease activity. One mechanism for excess NO production in MPL/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 (PPAR gamma). We demonstrate that renal PPAR gamma protein expression was altered as disease progressed in MRL/Ipr mice, which paralleled increased iNOS protein expression. Additionally, MRL/lpr-derived primary mesangial cells expressed less PPAR gamma than BALB/c mesangial cells and produced more NO in response to LPS and IFN gamma. Furthermore, PPAR gamma 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 PPAR gamma, further exacerbating the disease state. Published by Elsevier Inc.