{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:03:30Z","timestamp":1790971410321,"version":"4.1.0"},"reference-count":34,"publisher":"American Physiological Society","issue":"4","funder":[{"name":"Veterans Affairs","award":["1IK2BX003839-01A1"],"award-info":[{"award-number":["1IK2BX003839-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:p> 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<jats:sup>\u2212\/\u2212<\/jats:sup>)] 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<jats:sub>4<\/jats:sub> hydrolase (LTA<jats:sub>4<\/jats:sub>H) and LTC<jats:sub>4<\/jats:sub> synthase (LTC<jats:sub>4<\/jats:sub>S), are responsible for the synthesis of LTB<jats:sub>4<\/jats:sub> and cysteinyl LTs, respectively. Fibrosis was reduced after UUO in Ltc4s<jats:sup>\u2212\/\u2212<\/jats:sup>, but not Lta4h<jats:sup>\u2212\/\u2212<\/jats:sup>, mice. In contrast, using the folate nephropathy model, we found reduced fibrosis and improved renal function in both Ltc4s<jats:sup>\u2212\/\u2212<\/jats:sup> and Lta4h<jats:sup>\u2212\/\u2212<\/jats:sup> mice. In summary, our studies suggest that manipulation of the 5-LO pathway may represent a novel treatment approach for chronic kidney disease. <\/jats:p>","DOI":"10.1152\/ajprenal.00262.2018","type":"journal-article","created":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T18:16:37Z","timestamp":1547662597000},"page":"F732-F742","source":"Crossref","is-referenced-by-count":27,"title":["Inhibition of 5-lipoxygenase decreases renal fibrosis and progression of chronic kidney disease"],"prefix":"10.1152","volume":"316","author":[{"given":"John R.","family":"Montford","sequence":"first","affiliation":[{"name":"Division of Renal Diseases and Hypertension, University of Colorado-Anschutz Medical Campus, Denver, Colorado"},{"name":"Department of Medicine, University of Colorado-Anschutz Medical Campus, Denver, Colorado"},{"name":"Eastern Colorado Veterans Affairs Hospital, Denver, 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