Bone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3^KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.

骨产生的成纤维细胞生长因子 23 (FGF23) 会随着炎症和缺铁的反应而增加，并导致慢性肾脏病 (CKD) 的心血管死亡率。中性粒细胞明胶酶相关脂质运载蛋白（NGAL 或脂质运载蛋白 2；LCN2 是小鼠的同源物）是一种促炎和铁穿梭分子，其分泌是为了应对肾损伤，并可能促进 CKD 进展。我们通过循环 LCN2 研究了骨 FGF23 调节。在 23 周时，Col4a3 ^KO小鼠表现出肾功能受损、肾脏和血清 LCN2 水平升高、骨骼和血清 FGF23 增加、贫血和左心室肥大 (LVH)。Lcn2的删除在 CKD 小鼠中，它不会改善肾功能或贫血，但会阻止 LVH 的发展并改善与血清 FGF23 显着降低相关的存活率。Lcn2缺失特异性地阻止了 FGF23 对炎症的反应，但不是缺铁或磷酸盐，并且 LCN2 的施用通过激活骨细胞中 cAMP 介导的信号传导刺激Fgf23转录来增加健康和 CKD 小鼠的血清 FGF23。这些结果表明，肾脏产生的 LCN2 是骨骼响应炎症和 CKD 产生 FGF23 增加的重要介质。LCN2 抑制可能是降低 FGF23 和改善 CKD 结果的潜在治疗方法。