Role of the high-affinity leukotriene B.sub.4 receptor signaling in fibrosis after unilateral ureteral obstruction in mice

Leukotriene B.sub.4 (LTB.sub.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.sub.4 receptor BLT1 during development of kidney fibrosis induced by unilateral ureteral obstruction (UUO) in wild-type (WT) mice and BLT1 knockout (BLT1.sup.-/-) mice. We found elevated expression of 5-lipoxygenase (5-LOX), which generates LTB.sub.4, in the renal tubules of UUO kidneys from WT mice and BLT1.sup.-/- mice. Accumulation of immunoreactive type I collagen in WT UUO kidneys increased over time; however, the increase was less prominent in BLT1.sup.-/- UUO kidneys. Accumulation of S100A4-positive fibroblasts increased temporally in WT UUO kidneys, but was again less pronounced in-BLT1.sup.-/- UUO kidneys. The same was true of mRNA encoding transforming growth factor-[beta] (TGF)-[beta] and fibroblast growth factor (FGF)-2. Finally, accumulation of F4/80-positive macrophages, which secrete TGF-[beta], increased temporally in WT UUO and BLT1.sup.-/- UUO kidneys, but to a lesser extent in the latter. Following LTB.sub.4 stimulation in vitro, macrophages showed increased expression of mRNA encoding TGF-[beta]/FGF-2 and Col1a1, whereas L929 fibroblasts showed increased expression of mRNA encoding [alpha] smooth muscle actin (SMA). Bone marrow (BM) transplantation studies revealed that the area positive for type I collagen was significantly smaller in BLT1.sup.-/- BM[right arrow]WT than in WT-BM[right arrow]WT. Thus, LTB.sub.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.