PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

Urinary excretion of lipocalin-type PGD₂ synthase (L-PGDS), which converts PG H₂ to PGD₂, 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 PGD₂ 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 PGD₂ might be a strategy to slow the progression of renal fibrosis in CKD.Kidney failure is a public health problem worldwide, with increasing incidence and prevalence, high costs, and poor outcomes. CKD is generally progressive, incurable, and ultimately fatal, although some patients resolve with little or no sequelae. Because current treatment is basically limited to slowing the progression to ESRD using angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, more efficient therapies with different or additional modes of action are clearly needed.Regardless of disease etiology, tubulointerstitial fibrosis is the common pathway leading to ESRD in many kidney diseases and is regarded as a prognostic factor for renal function.^1–3 It is noteworthy that some clinical trials are proving that antifibrotic therapies, such as pirfenidone against diabetic nephropathy,⁴ are also effective for CKD. Therefore, elucidating the etiological mechanism underlying renal fibrosis and developing novel therapeutic strategies remains a serious, unmet medical need.Lipocalin-type PGD₂ synthase (L-PGDS) is a secretary protein of the lipocalin superfamily that converts PG H₂, a common precursor of prostanoids, to PGD₂. Because the urinary excretion of L-PGDS increases in the early stage of diabetic nephropathy,^5,6 as well as in patients with essential hypertension without any apparent renal injury,⁷ urinary L-PGDS may be an early diagnostic marker of renal injury in these patients. There is evidence indicating that, in the monkey kidney, L-PGDS is synthesized de novo in the loop of Henle, podocytes, and Bowman’s capsule of the glomeruli.⁸ Furthermore, L-PGDS gene expression in the tubular epithelium was increased in adriamycin-induced nephropathy.⁹ These findings suggest that, under conditions of tubulointerstitial stress, locally produced L-PGDS may be involved in the development of CKD. However, the precise pathophysiological significance of L-PGDS in the kidney remains to be determined.PGD₂ interacts with two receptors, the prostanoid DP₁ receptor and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Activation of the DP₁ receptor by PGD₂ has been shown to produce vasodilation¹⁰ and bronchodilation.¹¹ Furthermore, the DP₁ receptor is expressed by certain leukocyte populations,^12,13 including dendritic cells, where it controls various functions, including cytokine production. CRTH2 was originally identified as an orphan receptor expressed by Th2 lymphocytes. CRTH2 is not structurally related to the DP₁ receptor and belongs to the family of chemokine receptors. Activation of CRTH2 by PGD₂ plays an important role in allergic inflammation via the recruitment of Th2 lymphocytes and other leukocytes¹⁴ and, perhaps more importantly, by driving the production of the Th2 cytokines IL-4, IL-5, and IL-13.¹⁵