Role of the high-affinity leukotriene B4receptor signaling in fibrosis after unilateral ureteral obstruction in mice

Leukotriene B 4 (LTB 4 ) is a lipid mediator that acts as a potent chemoattractant for inflammatory leukocytes. Kidney fibrosis is caused by migrating inflammatory cells and kidney-resident cells. Here, we examined the role of the high-affinity LTB 4 receptor BLT1 during development of kidney fibrosis in wild-type (WT) mice and BLT1 knockout (BLT1 -/- ) mice with unilateral ureteral obstruction (UUO). We found elevated expression of 5-lipoxygenase (5-LOX), which generates LTB 4 , in the renal tubules of WT and BLT1 -/- UUO mice. Accumulation of immunoreactive type I collagen in UUO kidneys of WT mice increased over time; however, the increase was less prominent in BLT1 -/- mice. Accumulation of S100A4-positive fibroblasts also increased temporally in WT UUO kidneys, but was again less pronounced in those of BLT1 -/- mice. The same was true of mRNA encoding transforming growth factor-β (TGF)-β and fibroblast growth factor (FGF)-2. Finally, accumulation of F4/80-positive macrophages, which secrete TGF-β, also increased temporally in WT UUO and BLT1 -/- kidneys, but to a lesser extent in the latter. Following LTB 4 stimulation in vitro , macrophages showed increased expression of mRNA encoding TGF-β/FGF-2 and Col1a1, whereas L929 fibroblasts showed increased expression of mRNA encoding α smooth muscle actin (SMA). Bone marrow (BM) transplantation studies revealed that the area positive for type I collagen was significantly smaller in BLT1 -/- -BM→WT UUO kidneys than in WT-BM→WT kidneys. Thus, LTB 4 -BLT1 signaling plays a critical role in fibrosis in UUO kidneys by increasing accumulation of macrophages and fibroblasts. Therefore, blocking BLT1 may prevent renal fibrosis.