Inhibition of 5-lipoxygenase decreases renal fibrosis and progression of chronic kidney disease

Am J Physiol Renal Physiol. 2019 Apr 1;316(4):F732-F742. doi: 10.1152/ajprenal.00262.2018. Epub 2019 Jan 16.


In inflammatory diseases, the 5-lipoxygenase (5-LO) pathway contributes to epithelial damage and fibrosis by catalyzing the production of leukotrienes (LTs). Antagonists of the 5-LO pathway are currently approved for use in patients and are well tolerated. We found that expression of 5-LO is strongly induced in three models of chronic kidney disease: unilateral ureteral obstruction (UUO), folate nephropathy, and an orthologous mouse model of polycystic kidney disease. Immunohistochemistry showed that macrophages are the dominant source of 5-LO. Zileuton, a US Food and Drug Administration-approved antagonist of 5-LO, significantly reduced fibrosis at 7 and 14 days after UUO; these findings were confirmed using a genetically modified [5-LO-associated protein-knockout ( Alox5ap-/-)] mouse strain. Inhibition of 5-LO did not appear to change infiltration of leukocytes after UUO as measured by flow cytometry. However, fluorescence-lifetime imaging microscopy showed that 5-LO inhibitors reversed the glycolytic switch in renal tubular epithelial cells after UUO. Two downstream enzymes of 5-LO, LTA4 hydrolase (LTA4H) and LTC4 synthase (LTC4S), are responsible for the synthesis of LTB4 and cysteinyl LTs, respectively. Fibrosis was reduced after UUO in Ltc4s-/-, but not Lta4h-/-, mice. In contrast, using the folate nephropathy model, we found reduced fibrosis and improved renal function in both Ltc4s-/- and Lta4h-/- mice. In summary, our studies suggest that manipulation of the 5-LO pathway may represent a novel treatment approach for chronic kidney disease.

Keywords: 5-lipoxygenase; fibrosis; fluorescence-lifetime imaging microscopy; kidney; leukotrienes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / genetics
  • Fibrosis
  • Kidney / pathology*
  • Kidney Tubules / pathology
  • Lipoxygenase Inhibitors / therapeutic use*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polycystic Kidney Diseases / drug therapy
  • Receptors, Leukotriene / genetics
  • Receptors, Leukotriene / metabolism
  • Renal Insufficiency, Chronic / chemically induced
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / pathology*
  • Signal Transduction / drug effects
  • Ureteral Obstruction / drug therapy
  • Ureteral Obstruction / etiology


  • Lipoxygenase Inhibitors
  • Receptors, Leukotriene
  • leukotriene C4 receptor
  • Arachidonate 5-Lipoxygenase