RRC ID 60017
Author Kamata M, Amano H, Ito Y, Fujita T, Otaka F, Hosono K, Kamata K, Takeuchi Y, Yokomizo T, Shimizu T, Majima M.
Title Role of the high-affinity leukotriene B4 receptor signaling in fibrosis after unilateral ureteral obstruction in mice.
Journal PLoS One
Abstract Leukotriene B4 (LTB4) 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 LTB4 receptor BLT1 during development of kidney fibrosis induced by unilateral ureteral obstruction (UUO) in wild-type (WT) mice and BLT1 knockout (BLT1-/-) mice. We found elevated expression of 5-lipoxygenase (5-LOX), which generates LTB4, in the renal tubules of UUO kidneys from WT mice and BLT1-/- mice. Accumulation of immunoreactive type I collagen in WT UUO kidneys increased over time; however, the increase was less prominent in BLT1-/- UUO kidneys. Accumulation of S100A4-positive fibroblasts increased temporally in WT UUO kidneys, but was again less pronounced in-BLT1-/- UUO kidneys. 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, increased temporally in WT UUO and BLT1-/- UUO kidneys, but to a lesser extent in the latter. Following LTB4 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 than in WT-BM→WT. Thus, LTB4-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.
Volume 14(2)
Pages e0202842
Published 2019-1-1
DOI 10.1371/journal.pone.0202842
PII PONE-D-18-23121
PMID 30818366
PMC PMC6394974
MeSH Animals Apoptosis / physiology Fibroblasts / metabolism Fibroblasts / pathology Fibrosis / metabolism Kidney / metabolism Kidney Diseases / genetics Kidney Diseases / metabolism Kidney Diseases / pathology Kidney Tubules / metabolism Kidney Tubules / pathology Macrophages / metabolism Macrophages / pathology Male Mice Mice, Inbred C57BL Mice, Knockout Receptors, Leukotriene B4 / genetics Receptors, Leukotriene B4 / metabolism* Signal Transduction Ureteral Obstruction / genetics* Ureteral Obstruction / metabolism* Ureteral Obstruction / pathology
IF 2.776
Times Cited 2
Human and Animal Cells L929