title: PGD2-CRTH2 pathway promotes tubulointerstitial fibrosis.
abstract: Urinary excretion of lipocalin-type PGD(2) synthase (L-PGDS), which converts PG H(2) to PGD(2), increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD(2) contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD(2) might be a strategy to slow the progression of renal fibrosis in CKD.
authors.affiliation: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. hideyuki.ito@jikei.ac.jp
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ito
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Yan
authors.forename: Nanae
authors.initials: N
authors.lastname: Nagata
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Utsunomiya
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D005355:Fibrosis; D006801:Humans; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015230:Prostaglandin D2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014517:Ureteral Obstruction / Q000150:complications / Q000378:metabolism
chemical_list: C533609:CAY 10471; D002227:Carbazoles; D018793:Interleukin-13; D054834:Lipocalins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; D015847:Interleukin-4; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor