A Comparative Transcriptome Analysis Identifying FGF23 Regulated Genes in the Kidney of a Mouse CKD Model

Bing Dai, Valentin David, Aline Martin, Jinsong Huang, Hua Li, Yan Jiao, Weikuan Gu, Leigh Quarles

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Abstract

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.

Original languageEnglish (US)
Article numbere44161
JournalPLoS One
Volume7
Issue number9
DOIs
StatePublished - Sep 6 2012

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fibroblast growth factors
disease models
Gene Expression Profiling
kidney diseases
transcriptomics
Chronic Renal Insufficiency
Genes
kidneys
Kidney
mice
genes
renal failure
fibroblast growth factor 23
Renal Insufficiency
transforming growth factor beta 2
animal models
Lipocalins
renin-angiotensin system
Fibroblast Growth Factor Receptors
peptidyl-dipeptidase A

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

A Comparative Transcriptome Analysis Identifying FGF23 Regulated Genes in the Kidney of a Mouse CKD Model. / Dai, Bing; David, Valentin; Martin, Aline; Huang, Jinsong; Li, Hua; Jiao, Yan; Gu, Weikuan; Quarles, Leigh.

In: PLoS One, Vol. 7, No. 9, e44161, 06.09.2012.

Research output: Contribution to journalArticle

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