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

In inflammatory diseases, the 5-lipoxygenase (5-LO) pathway contributes to epithelial damage and fibrosis by catalyzing the production of leukotrienes. 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, an FDA-approved antagonist of 5-LO, significantly reduced fibrosis at both 7 and 14 days post-UUO; these findings were confirmed using a genetically modified mouse strain (Alox5ap -/- mice). Inhibition of 5-LO did not appear to change infiltration of leukocytes after UUO as measured by flow cytometry. However, fluorescent lifetime imaging microscopy (FLIM) showed that 5-LO inhibitors reversed the glycolytic switch in renal tubular epithelial cells after UUO. Tw...