%0 Journal Article
%T PPAR Agonist Rosiglitazone Suppresses Renal mPGES-1/PGE2 Pathway in db/db Mice
%A Ying Sun
%A Zhanjun Jia
%A Gang Liu
%A Li Zhou
%A Mi Liu
%A Baoxue Yang
%A Tianxin Yang
%J PPAR Research
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/612971
%X Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR)¦Ã and PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPAR¦Ã activation on renal mPGES-1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN. 1. Introduction The abnormality of renal prostaglandins in diabetic kidney was thought to be an important factor in mediating the glomerular injury, tubular interstitial fibrosis, and fluid imbalance [1¨C4]. Among five prostanoids of PGE2, PGD2, PGI2, PGF2¦Á, and thromboxane (TX) A2, PGI2 and TXA2 are important players in regulation of renal hemodynamics [5¨C7]; PGE2 serves as an important regulator of glomerular integrity, SS hemodynamics, and tubular fluid reabsorption [8¨C10], while the PGD2 and PGF2¦Á in kidney are less studied and their functions are poorly understood. The renal PGE2 receptor (EP1-EP4) expression profile is altered in type-1 diabetic mice [11]. Makino et al. demonstrated that EP1-selective antagonist prevented the progression of nephropathy in streptozotocin (STZ) diabetic rats [12]. Most recently, Mohamed et al. reported that EP4 agonist exacerbated kidney injury in STZ-induced type-1 diabetes in mice [13]. These reports strongly suggested a detrimental role of PGE2 in kidney of STZ-induced type-1 diabetes via EP1 and/or EP4 receptors. However, no prior studies examine the role of PGE synthase in the kidney injury of type-2 diabetes. In clinic, type-2
%U http://www.hindawi.com/journals/ppar/2013/612971/