Role of the high-affinity leukotriene B4 receptor signaling in fibrosis after unilateral ureteral obstruction in mice

PLoS One. 2019 Feb 28;14(2):e0202842. doi: 10.1371/journal.pone.0202842. eCollection 2019.

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.

MeSH terms

  • 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

Substances

  • Ltb4r1 protein, mouse
  • Receptors, Leukotriene B4

Grant support

The authors received no specific funding for this work.