PGD2-CRTH2 pathway promotes tubulointerstitial fibrosis.

Journal of the American Society of Nephrology : JASN 2012 Nov

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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.

Citation

Hideyuki Ito, Xiaoxiang Yan, Nanae Nagata, Kosuke Aritake, Yoshinori Katsumata, Tomohiro Matsuhashi, Masataka Nakamura, Hiroyuki Hirai, Yoshihiro Urade, Koichiro Asano, Masato Kubo, Yasunori Utsunomiya, Tatsuo Hosoya, Keiichi Fukuda, Motoaki Sano. PGD2-CRTH2 pathway promotes tubulointerstitial fibrosis. Journal of the American Society of Nephrology : JASN. 2012 Nov;23(11):1797-809