Ppar Alpha Activation By Mhy908 Attenuates Age-Related Renal Inflammation Through Modulation Of The Ros/Akt/Fox01 Pathway

2.44-(5-Chlorobenzothiazothiazol-2-y1)phenoxy]-2-methyl-propionic acid (MHY908) has been shown to prevent insulin resistance-induced hyperinsulinemia in aged rats. However, the mechanism underlying MHY908mediated amelioration of renal inflammation with insulin resistance during aging remains unknown. This study investigated the effects of MHY908 on age-related changes in the IRS/Akt/forkhead box (FoxO) I signaling pathway in the kidneys of aged rats and HEK293T cells. Experiments were performed in young, old, and MHY908-fed old rats (1 mg or 3 mg/kg/day MHY908 for 4 weeks). We found that MHY908-fed old rats suppressed phosphorylation of IRS/Akt and induced Fox01 activation, leading to increased expression of MnSOD and catalase. In addition, in insulin -treated cells, MHY908 prevented the Fox01 inactivation and increased the expression of MnSOD and catalase by inactivating IRS and Akt. In contrast, NF-kappa B signaling pathway decreased with MHY908 treatment in insulin -treated cells. Furthermore, MHY908 exclusively activated peroxisome proliferator-activated receptor (PPAR) a in the kidneys, leading to the inhibition of insulin-induced NADPH oxidase subunit 4 (NOX4)-derived reactive oxygen species (ROS) generation and Fox01 inactivation. In conclusion, MHY908 improved the hyperinsulinemia-induced pro-inflammatory response through NF-kappa B inactivation and Fox01 activation in aged rat kidneys. These phenomena suggest that PPAR alpha activation by MHY908 attenuates NOX4-derived ROS generation in response to insulin. (C) 2017 Elsevier Inc. All rights reserved.