FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts

Edward R Smith,Sven-Jean Tan,Tim D Hewitson,Stephen G Holt

doi:10.1038/s41598-017-02709-w

Edward R Smith, Sven-Jean Tan + Show 2 more

Open Access

https://doi.org/10.1038/s41598-017-02709-w

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Abstract

In kidney disease, higher circulating levels of the mineral-regulating hormone fibroblast growth factor (FGF)-23 are predictive of disease progression but direct pathogenic effects on the kidney are unknown. We sought evidence of local renal synthesis in response to unilateral ureteric obstruction in the mouse, and pro-fibrotic actions of FGF23 on the fibroblast in vitro. Acute tubulointerstitial injury due to unilateral ureteric obstruction stimulated renal FGF23 synthesis by tubules, and downregulated inactivating proprotein convertases, without effects on systemic mineral metabolism. In vitro, FGF23 had divergent effects on fibroblast activation in cells derived from normal and obstructed kidneys. While FGF23 failed to stimulate fibrogenesis in normal fibroblasts, in those primed by injury, FGF23 induced pro-fibrotic signalling cascades via activation of TGF-β pathways. Effects were independent of α-klotho. Tubule-derived FGF23 may amplify myofibroblast activation in acute renal injury, and might provide a novel therapeutic target in renal fibrosis.

Highlights

Fibroblast growth factor 23 (FGF23) is a bone-derived member of the endocrine fibroblast growth factor (FGF) family known to regulate mineral metabolism principally through effects in the kidney and parathyroid glands[1]
Whether elevated FGF23 concentrations serve as a surrogate for derangements in mineral metabolism that are associated with outcome, or are directly involved in the pathogenesis of cardiovascular disease (CVD) or Chronic Kidney Disease (CKD) is widely debated but unproven
We have identified temporal and spatial changes in renal FGF23 expression in response to acute ureteric obstruction (UUO)

Summary

Introduction

Fibroblast growth factor 23 (FGF23) is a bone-derived member of the endocrine FGF family known to regulate mineral metabolism principally through effects in the kidney and parathyroid glands[1]. FGF23 levels rise early in Chronic Kidney Disease (CKD), predominantly as intact protein[3], and generally precede changes in other mineral metabolites[5]. The cause of intact FGF23 excess seen in CKD is complex and likely to include increased osteocytic production in response to local changes in mineralisation[17, 18], inflammation and functional iron deficiency via hypoxia inducible factor (HIF)1α activation[19], and altered handling by the kidney[20]. Comparative transcriptome analysis of kidney tissue from CKD and non-CKD models of FGF23 excess have identified the activation of common pathways associated with fibrosis and inflammation, including transforming growth factor (TGF)-β1 related signalling[30], a master regulator of fibrosis[31]

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