Division of Renal Diseases and Hypertension, University of Colorado-Anschutz Medical Campus , Denver, Colorado.
Department of Medicine, University of Colorado-Anschutz Medical Campus , Denver, Colorado.
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, LTA hydrolase (LTAH) and LTC synthase (LTCS), are responsible for the synthesis of LTB 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.
在炎症性疾病中，5-脂氧合酶（5-LO）途径通过催化白三烯（LTs）的产生而导致上皮损伤和纤维化。5-LO 途径的拮抗剂目前已被批准用于患者，且耐受性良好。我们发现，在三种慢性肾脏病模型中，5-LO 的表达被强烈诱导：单侧输尿管梗阻（UUO）、叶酸肾病和同源小鼠多囊肾病模型。免疫组织化学显示，巨噬细胞是 5-LO 的主要来源。5-LO 的美国食品和药物管理局批准的拮抗剂齐留通（Zileuton）在 UUO 后 7 天和 14 天显著减少纤维化；这些发现通过一种基因修饰的[5-LO 相关蛋白敲除（Alox5ap）]小鼠品系得到了证实。通过流式细胞术测量，抑制 5-LO 似乎并没有改变 UUO 后白细胞的浸润。然而，荧光寿命成像显微镜显示，5-LO 抑制剂在 UUO 后逆转了肾小管上皮细胞的糖酵解开关。5-LO 的两个下游酶，LTA 水解酶（LTAH）和 LTC 合酶（LTCS），分别负责 LTB 和半胱氨酰 LTs 的合成。在 UUO 后，Ltc4s 小鼠的纤维化减少，但 Lta4h 小鼠则不然。相比之下，使用叶酸肾病模型，我们发现 Ltc4s 和 Lta4h 小鼠的纤维化减少和肾功能改善。总之，我们的研究表明，5-LO 途径的调控可能代表一种治疗慢性肾脏病的新方法。
