Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease

Guillaume Courbon,Samantha Neuburg,Emily Lynch,Aline Martin,Connor Francis,Myles Wolf,Tamara Isakova,Xueyan Wang,Claire Gerber,Jodie L Babitt,Valentin David

doi: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.

Highlights

Bone production of fibroblast growth factor 23 (FGF23) is increased in patients and animals with chronic kidney disease (CKD)[1,2,3] and is associated with the development of left ventricular hypertrophy (LVH), heart failure, and mortality.[1,2,4,5,6,7] Excess circulating FGF23 is the first major perturbation of mineral metabolism that occurs in CKD, the complex mechanisms that trigger elevations of FGF23 in CKD remain incompletely understood
Increased serum neutrophil gelatinase-associated lipocalin in humans (NGAL) is associated with excess FGF23 in patients with CKD NGAL/LCN2 is a secreted pro-inflammatory and iron shuttling glycoprotein which might contribute to the progression of CKD.[31]
Given that FGF23 production is increased in response to inflammation and iron deficiency, we investigated whether FGF23 levels correlate with circulating NGAL

Summary

RESULTS

Increased serum NGAL is associated with excess FGF23 in patients with CKD NGAL/LCN2 is a secreted pro-inflammatory and iron shuttling glycoprotein which might contribute to the progression of CKD.[31]. Deletion of Lipocalin 2 reduces FGF23 production in CKD Total cFGF23 and iFGF23 levels were similar in Lcn2KO and WT mice (Fig. 3i, j) at 23 weeks of age This was accompanied by normal urine Pi excretion and serum phosphate (Fig. 3k, l). Serum cFGF23 and iFGF23 levels were highly increased in Col4a3KO mice with advanced CKD (Fig. 3i, j), which showed hyperphosphatemia with increased urine Pi excretion (Fig. 3k, l) These changes were markedly attenuated by Lcn[2] deletion in Col4a3KO mice, which demonstrated 60% reductions in serum cFGF23 and iFGF23, 80% reduction in bone Fgf[23] mRNA expression (Fig. 3i, j, m), and significantly reduced urine Pi excretion in CPD mice (Fig. 3k) and serum phosphate levels decreased in CPD mice (Fig. 3l). Despite the role of LCN2 as an iron transporter, Lcn2KO mice showed similar increases in both serum cFGF23 and iFGF23 levels to WT mice in response to a low iron diet (Fig. 5c, d), suggesting that LCN2

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DISCUSSION

MATERIALS AND METHODS