title: A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model.
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.
authors.affiliation: University of Tennessee Health Science Center, Medicine-Nephrology, Memphis, Tennessee, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Dai
authors.forename: Valentin
authors.initials: V
authors.lastname: David
authors.forename: Aline
authors.initials: A
authors.lastname: Martin
authors.forename: Jinsong
authors.initials: J
authors.lastname: Huang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiao
authors.forename: Weikuan
authors.initials: W
authors.lastname: Gu
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D016000:Cluster Analysis; D024141:Collagen Type IV / Q000172:deficiency / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000235:genetics* / Q000473:pathology; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C000717428:Fgf23 protein, mouse; D012333:RNA, Messenger; C057112:type IV collagen alpha3 chain; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23