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.

Interleukin-4 Induces Senescence in Human Renal Carcinoma Cell Lines through STAT6 and p38 MAPK

“…In lupusprone mice, STAT6 deficiency or anti-IL-4 Ab treatment ameliorates kidney disease, particularly glomerulosclerosis (53). Additionally, unilateral urethral obstruction induced tubulointerstitial fibrosis, which was ameliorated by knock-out of IL-4 and IL-13 (54). In our microarray data, expression levels of genes implicated in renal diseases, such as collagen VI, IL-6, LTBP1, and SOCS1, were markedly induced by IL-4 ( Table 1), suggesting that IL-4 might play a crucial role in the progression of renal disease.…”

Enalapril treatment increases T cell number and promotes polarization towards M1-like macrophages locally in diabetic nephropathy

“…Interestingly, IL-4 and IL-13 stimulation in human macrophages, which promotes M2 polarization, increases ACE expression while LPS and IFN-γ stimulation, which promotes M1 polarization reduce ACE expression in macrophages [60]. Further, Ito et al elegantly demonstrated that these Th2-associated cytokines (IL-4, IL-13 and PDE2) not only promote the development of M2-macrophages, but also were essential for the fibrotic responses in UUO kidney models in mice [61]. Hence ACE inhibition in vivo may counteract production of Th2/M2 associated cytokines thereby promoting a sustained M1 macrophage population.…”

Role of cyclooxygenase-2 in the development of interstitial fibrosis in kidneys following unilateral ureteral obstruction in mice

“…ONO-1301 protected UUO kidneys against fibrosis via the induction of HGF, an antifibrotic factor that counteracts TGF-b [25]. In addition, PGD 2 has been suggested to slow the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes [26].…”