2022 Fiscal Year Final Research Report

Novel therapeutic agents for kidney disease targeting the FGF23-Klotho system

Research Project

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Project/Area Number	20K08613
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 53040:Nephrology-related
Research Institution	Jichi Medical University
Principal Investigator	Iwazu Yoshitaka 自治医科大学, 医学部, 准教授 (40424014)
Co-Investigator(Kenkyū-buntansha)	黒尾誠自治医科大学, 医学部, 教授 (10716864) 黒須洋自治医科大学, 医学部, 准教授 (40468690)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	FGF23 / 急性腎障害 / Klotho / 慢性腎臓病
Outline of Final Research Achievements	In acute kidney injury (AKI) and chronic kidney disease (CKD), reduced renal Klotho protein expression was contributed to renal injury. In this study, we investigated whether FGF (Fibroblast Growth Factor) 23 is involved in the development and progression of renal injury via the decreased renal klotho protein expression by the administration of novel agent, FGF23 inhibitory peptide (ΔN) for AKI or CKD model. In AKI model, the treatment with ΔN suppressed the down-regulation of renal klotho protein and significantly improved renal injury at 24 h post ischemia-reperfusion; Klotho-deficient mice did not improve renal injury by the administration of ΔN, and thus the inhibition of FGF23 by ΔN could ameliorate the kidney injury via the maintenance of renal Klotho protein expression. In CKD model (high phosphate diet-fed mice), the continuous administration of ΔN using a minipump in CKD model did not significantly improve renal injury including fibrosis and calcification.
Free Research Field	腎臓病
Academic Significance and Societal Importance of the Research Achievements	AKIにおける血清FGF23上昇はその発症に対して独立した危険因子である。我々は、FGF23を阻害するΔN投与がAKIモデルにおいて腎障害を軽減することをはじめて明らかにし、FGF23がAKIの病態に関与していることを示した。重症AKIモデルではFGF23投与により腎障害を軽減することが最近報告され、重症AKIではFGF23が保護的に働き、特に回復期の48時間後に有意差を認めることからAKIからの回復を促進している可能性が考えられる。AKIの病期（急性期なのか回復期なのか）や重症度に応じて、AKIにおいてFGF23が果たす役割が異なる可能性があり、臨床応用に向けて今後さらなる研究が必要である。