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Abstract: PO0530

Indoxyl Sulfate Induces Cardiomyocyte Hypertrophy via FGF23-FGFR4 Signaling Pathway

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Kishimoto, Hiroshi, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
  • Nakano, Toshiaki, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
  • Yamada, Shunsuke, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
  • Torisu, Kumiko, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
  • Tokumoto, Masanori, Japanese Red Cross Fukuoka Hospital, Fukuoka, Fukuoka, Japan
  • Taniguchi, Masatomo, Fukuoka renal clinic, Fukuoka, Fukuoka, Japan
  • Kitazono, Takanari, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
Background

Both fibroblast growth factor 23 (FGF23) and indoxyl sulfate (IS) have been reported to relate with left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD), but their inter-relationship remains unknown.

Methods

To induce LVH, 8-week-old-male C57BL/6J mice were fed high phosphorus diet after heminephrectomy for the induction of FGF23 and administrated with continuous subcutaneous dose of 100mg/kg IS per day for 4 weeks, and half of them were treated with continuous intraperitoneal administration dose of 7.5 mg/kg H3B-6527 (H3B), a fibroblast growth factor receptor 4 (FGFR4)- inhibitor. Moreover, rat cardiac myoblast (H9c2, 2-1) cells were incubated with 0, 0.25 or 1.0 mM IS and collected after 24 and 72 hours for RT-PCR and western blotting, respectively.

Results

IS promoted cardiac hypertrophy, and inhibition of FGFR4 reduced heart weight and left ventricular wall thickness in IS groups (p < 0.05). There was no significant difference in serum FGF23 level among experimental groups, but the expressions of FGF23 protein and mRNA in the heart were markedly increased in IS-injected mice compared to control mice (p < 0.05). In cultured H9c2 cells incubated with IS, intact FGF23 protein expression and phosphorylation of FGFR4 were elevated in cell lysate, but intact FGF23 protein level in the media didn’t change. The mRNA levels of β-myosin heavy chain (βMHC), α-smooth muscle actin (αSMA), brain natriuretic peptide (BNP), polypeptide N-acetylgalactosaminyltransferase 3 (Galnt3), and FGF23 were significantly up-regulated (p < 0.05), but collagen I was not.

Conclusion

IS increased intact FGF23 protein expression and activated FGF23-FGFR4 signaling in cardiomyocyte, leading to LVH, and FGFR4 inhibition suppressed IS-induced LVH.