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• W2910616615 abstract "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, LTA 4 hydrolase (LTA 4 H) and LTC 4 synthase (LTC 4 S), are responsible for the synthesis of LTB 4 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." @default.
• W2910616615 created "2019-01-25" @default.
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• W2910616615 date "2019-04-01" @default.
• W2910616615 modified "2023-10-16" @default.
• W2910616615 title "Inhibition of 5-lipoxygenase decreases renal fibrosis and progression of chronic kidney disease" @default.
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• W2910616615 doi "https://doi.org/10.1152/ajprenal.00262.2018" @default.
• W2910616615 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6483031" @default.
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