title: The PPARβ/δ agonist GW501516 attenuates peritonitis in peritoneal fibrosis via inhibition of TAK1-NFκB pathway in rats.
abstract: Peritoneal fibrosis is a common consequence of long-term peritoneal dialysis (PD), and peritonitis is a factor in its onset. Agonist-bound peroxisome proliferator-activated receptors (PPARs) function as key regulators of energy metabolism and inflammation. Here, we examined the effects of PPARβ/δ agonist GW501516 on peritonitis in a rat peritoneal fibrosis model. Peritoneal fibrosis secondary to inflammation was induced into uremic rats by daily injection of Dianeal 4.25% PD solutions along with six doses of lipopolysaccharide before commencement of GW501516 treatment. Normal non-uremic rats served as control, and all rats were fed with a control diet or a GW501516-containing diet. Compared to control group, exposure to PD fluids caused peritoneal fibrosis that was accompanied by increased mRNA levels of monocyte chemoattractant protein-1, tumor necrotic factor-α, and interleukin-6 in the uremic rats, and these effects were prevented by GW501516 treatment. Moreover, GW501516 was found to attenuate glucose-stimulated inflammation in cultured rat peritoneal mesothelial cells via inhibition of transforming growth factor-β-activated kinase 1 (TAK1), and nuclear factor kappa B (NFκB) signaling pathway (TAK1-NFκB pathway), a main inflammation regulatory pathway. In conclusion, inhibition of TAK1-NFκB pathway with GW501516 may represent a novel therapeutic approach to ameliorate peritonitis-induced peritoneal fibrosis for patients on PD.
authors: Department of Nephrology, Shengjing Hospital, China Medical University, 36 Sanhao Street, Shenyang, 110004, People's Republic of China.
authors: Xuesong
authors: X
authors: Su
authors: Guangyu
authors: G
authors: Zhou
authors: Yanqiu
authors: Y
authors: Wang
authors: Xu
authors: X
authors: Yang
authors: Li
authors: L
authors: Li
authors: Rui
authors: R
authors: Yu
authors: Detian
authors: D
authors: Li
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005947:Glucose; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D047494:PPAR delta / Q000819:agonists; D048068:PPAR-beta / Q000819:agonists; D010530:Peritoneal Dialysis / Q000009:adverse effects; D056627:Peritoneal Fibrosis / Q000188:drug therapy* / Q000473:pathology; D010538:Peritonitis / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014511:Uremia / Q000188:drug therapy / Q000473:pathology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D018932:Chemokine CCL2; D005947:Glucose; D051550:I-kappa B Kinase; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D047494:PPAR delta; D048068:PPAR-beta; D012333:RNA, Messenger; D013844:Thiazoles; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C491766:Ccl2 protein, rat; C425931:GW 501516; C498145:Rela protein, rat