The intrinsic prostaglandin E2–EP4 system of the renal tubular epithelium limits the development of tubulointerstitial fibrosis in mice

• DOI: 10.1038/ki.2012.115
• Publication Date: 2012-04-18T13:08:06Z
• Authors: Naoki Nakagawa; Koh-ichi Yuhki; Jun-ichi Kawabe; Takayuki Fujino; Osamu Takahata; Maki Kabara; Kazutoshi Abe; Fumiaki Kojima; Hitoshi Kashiwagi; Naoyuki Hasebe; Kenjiro Kikuchi; Yukihiko Sugimoto; Shuh Narumiya; Fumitaka Ushikubi
• Keywords: 0301 basic medicine; Mice, 129 Strain; Dinoprostone; prostaglandins; Mice; 03 medical and health sciences; Folic Acid; Animals; Chemokine CCL5; Cells, Cultured; Chemokine CCL2; Cell Proliferation; Macrophages; Connective Tissue Growth Factor; Epithelial Cells; renal fibrosis; Fibrosis; Heptanoates; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Kidney Tubules; Gene Expression Regulation; Nephrology; Cyclooxygenase 2; Kidney Diseases; chronic kidney disease

Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E(2) (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast proliferation. This was accompanied by an upregulation of COX-2 and PGE(2) receptor subtype EP(4) mRNAs. In the kidneys of EP(4) gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP(4)-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP(4)-knockout mice and suppressed by the EP(4) agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP(4) mRNA, were localized in renal tubular epithelial cells after ureteral obstruction. In cultured renal fibroblasts, another EP(4)-specific agonist significantly inhibited PDGF-induced proliferation and profibrotic connective tissue growth factor production. Hence, an endogenous PGE(2)-EP(4) system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses.