Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease
Open Access
- 2 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Bone Research
- Vol. 9 (1), 1-11
- https://doi.org/10.1038/s41413-021-00154-0
Abstract
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, Col4a3KO 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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102815, R01DK114158, R01DK101730, R01DK102815, R01DK114158, R01DK101730)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
This publication has 66 references indexed in Scilit:
- NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney diseaseKidney International, 2012
- Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM-1) as Predictors of Incident CKD Stage 3: The Atherosclerosis Risk in Communities (ARIC) StudyAmerican Journal of Kidney Diseases, 2012
- Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney diseaseJournal of Bone and Mineral Research, 2011
- Fibroblast Growth Factor 23 and Risks of Mortality and End-Stage Renal Disease in Patients With Chronic Kidney DiseaseJAMA, 2011
- The role of iron in the immune response to bacterial infectionImmunologic Research, 2010
- Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complexNature Chemical Biology, 2010
- A Mammalian Siderophore Synthesized by an Enzyme with a Bacterial Homolog Involved in Enterobactin ProductionCell, 2010
- Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney diseaseBone, 2009
- Neutrophil Gelatinase-associated Lipocalin Acts as a Protective Factor against H2O2 ToxicityArchives of Medical Research, 2008
- Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobinAmerican Journal of Kidney Diseases, 1999