PLoS ONE · 2012 · 192 citations · 78 references
MedicineMolecular GeneticsNephrologyGene ExpressionRenal PathophysiologyTranscriptional RegulationChronic Kidney DiseasePhosphate HomeostasisRenal DiseaseRenal Molecular PhysiologyRenal PhysiologyVitamin D MetabolismCkd ProgressionFgf23-klotho AxisFibroblast Growth Factor 23 DysregulationFibroblast Growth Factor Receptor SignalingKlotho DeficiencyKlotho FunctionKlotho SignalingKlotho-mediated Mineral Transport
Elevated circulating FGF23 is linked to cardiovascular complications and CKD progression, but pinpointing its direct renal targets is hampered by systemic mineral metabolism changes and intrinsic kidney pathology. The study aimed to identify kidney genes directly regulated by FGF23 that could explain its adverse effects in CKD. By performing comparative genome‑wide expression profiling across Col4a3−/−, Hyp, and FGF23 transgenic mice, the authors isolated FGF23‑responsive genes while minimizing confounding factors. The analysis showed that FGF23 suppresses α‑Klotho and ACE2 and induces inflammatory and fibrotic transcripts such as Lcn2, TGF‑β, and TNF‑α, providing mechanistic links to renal failure progression and cardiovascular disease.
Elevations of circulating Fibroblast growth factor 23 (FGF23) are associated with adverse cardiovascular outcomes and progression of renal failure in chronic kidney disease (CKD). Efforts to identify gene products whose transcription is directly regulated by FGF23 stimulation of fibroblast growth factor receptors (FGFR)/α-Klotho complexes in the kidney is confounded by both systemic alterations in calcium, phosphorus and vitamin D metabolism and intrinsic alterations caused by the underlying renal pathology in CKD. To identify FGF23 responsive genes in the kidney that might explain the association between FGF23 and adverse outcomes in CKD, we performed comparative genome wide analysis of gene expression profiles in the kidney of the Collagen 4 alpha 3 null mice (Col4a3−/−) model of progressive kidney disease with kidney expression profiles of Hypophosphatemic (Hyp) and FGF23 transgenic mouse models of elevated FGF23. The different complement of potentially confounding factors in these models allowed us to identify genes that are directly targeted by FGF23. This analysis found that α-Klotho, an anti-aging hormone and FGF23 co-receptor, was decreased by FGF23. We also identified additional FGF23-responsive transcripts and activation of networks associated with renal damage and chronic inflammation, including lipocalin 2 (Lcn2), transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) signaling pathways. Finally, we found that FGF23 suppresses angiotensin-converting enzyme 2 (ACE2) expression in the kidney, thereby providing a pathway for FGF23 regulation of the renin-angiotensin system. These gene products provide a possible mechanistic links between elevated FGF23 and pathways responsible for renal failure progression and cardiovascular diseases.
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Mutation of the mouse klotho gene leads to a syndrome resembling ageing.
PubMed · 1997 · 66.6K citations
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Makoto Kuro‐o, Yutaka Matsumura, Hiroki Aizawa et al. · Nature · 1997 · 3.8K citations
FGF23 induces left ventricular hypertrophy
Christian Faul, Ansel P. Amaral, Behzad N. Oskouei et al. · Journal of Clinical Investigation · 2011 · 2K citations