INTRODUCTION: 15-Lipoxygenase (15-LO) is a non-heme iron-containing dioxygenase that has both pro- and anti-inflammatory roles in many tissues and disease states. 15-LO is thought to influence macrophage phenotype; and silencing 15-LO reduces fibrosis after acute inflammatory triggers. The goal of this study was to determine if altering 15-LO expression influences inflammation and fibrogenesis in a murine model of unilateral ureteral obstruction (UUO). METHODS: C57BL/6J mice, 15-lipoxygenase knockout (Alox15-/-) mice, and 15-lipoxygenase transgenic overexpressing mice (15LOTG) were subjected UUO and kidneys were analyzed at 3, 10, and 14-days post injury. Histology for fibrosis, cytokine quantification, flow cytometry, and metabolomics were performed on injured tissues and controls. PD146176, a specific 15-LO inhibitor, was used to complement studies involving knockout animals. RESULTS: Compared to WT animals undergoing UUO, Alox15-/- mouse kidneys had less pro-inflammatory, pro-fibrotic message along with less fibrosis. PD146176 inhibited 15-LO, and resulted in reduced fibrosis similar to Alox15-/- mice. Flow cytometry revealed that Alox15-/- UUO-injured kidneys had a dynamic change in macrophage phenotype, with an early blunting of CD11bHiLy6CHi "M1" macrophages and increase in anti-inflammatory CD11bHiLy6CInt "M2c" macrophages and reduced expression of the fractalkine receptor, CX3CR1. Many of these findings were reversed when UUO was performed on 15LOTG mice. Metabolomics analysis revealed that WT kidneys developed a glycolytic shift post-injury, while Alox15-/- kidneys exhibited increased oxidative phosphorylation. CONCLUSIONS: 15-LO manipulation by genetic or pharmacologic means induces dynamic changes in the inflammatory microenvironment in the UUO-model and appears to be critical in the progression of UUO-induced fibrosis.