Promoting effect of circulating FGF23 on atrial fibrosis in chronic kidney disease

doi:10.11958/20240171

Abstract

Abstract:

Objective To explore the possible mechanisms by which fibroblast growth factor (FGF) 23 promoted atrial fibrosis in circulation of chronic kidney disease (CKD) by binding to atrial tissue fibroblast growth factor receptor (FGFR) 4. Methods Twenty-two healthy male Sprague-Dawley (SD) rats were selected. Rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model (n=14). The remaining 8 rats were used as the sham group. The sham group (n=8) underwent the same surgery without removing renal tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography and pathological indices were monitored in both groups. Enzyme-linked immunosorbent assay (ELISA) method was used to determine the circulating levels of FGF23 in the two groups of rats. Transcriptomic analysis of left atrial tissue was performed to search for differentially expressed genes. Rat atrial fibroblasts were divided into the control group, the FGFR inhibitor group, the transforming growth factor-β (TGF-β) group and the TGF-β+FGFR inhibitor group. The expression levels of α-smooth muscle actin (α-SMA), collagenⅠ (Col Ⅰ) and phosphorylated protein kinase B (p-AKT) protein were detected by Western blot assay. Results Systolic blood pressure, blood urea nitrogen and creatinine were elevated in the CKD group of rats. Cardiac electrophysiological study showed that CKD could promote the occurrence of atrial fibrillation (AF) and atrioventricular block. Cardiac ultrasound suggested that the internal diameter of the left atrium was significantly increased in rats of the CKD group. Pathological findings showed that the left atrium in the CKD group underwent significant fibrosis, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. These changes were accompanied by higher circulating FGF23. Western blot results showed that FGFR4 expression was upregulated in the CKD group. After blocking the FGF23/FGFR4 signaling pathway in atrial fibroblasts, the fibrosis-related proteins α-SMA, Col Ⅰ and p-AKT/AKT were decreased. Conclusion CKD promotes the occurrence of AF by inducing both structural and electrical remodeling. Increased circulating FGF23 promotes atrial fibrosis by activating the downstream AKT pathway binding to FGFR4 in atrial tissue.

Key words: kidney diseases, atrial fibrillation, fibrosis, atrial remodeling, fibroblast growth factors, receptors, fibroblast growth factor

CLC Number:

R541.75

Figures/Tables 15

References 25

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组别	体质量/g		Cr/ （μmol/L）		BUN/ （mmol/L）		收缩压/ mmHg
SHAM组	485.60±38.28		23.57±8.18		168.09±8.66		114.17±4.78
CKD组	502.80±28.88		58.05±13.57		245.09±19.83		126.17±6.11
t	0.802		4.866^＊＊		7.955^＊＊		3.460^＊＊
组别		平均动脉压/ mmHg		舒张压/ mmHg		心脏质量/胫骨长度/（mg/cm）
SHAM组		100.73±2.31		93.94±3.28		31.20±4.04
CKD组		103.42±8.86		93.68±9.86		44.41±4.46
t		0.657		0.057		4.907^＊＊

组别	体质量/g		Cr/ （μmol/L）		BUN/ （mmol/L）		收缩压/ mmHg
SHAM组	485.60±38.28		23.57±8.18		168.09±8.66		114.17±4.78
CKD组	502.80±28.88		58.05±13.57		245.09±19.83		126.17±6.11
t	0.802		4.866^＊＊		7.955^＊＊		3.460^＊＊
组别		平均动脉压/ mmHg		舒张压/ mmHg		心脏质量/胫骨长度/（mg/cm）
SHAM组		100.73±2.31		93.94±3.28		31.20±4.04
CKD组		103.42±8.86		93.68±9.86		44.41±4.46
t		0.657		0.057		4.907^＊＊

组别	QT间期/ms	窦房结恢复时间/ms	房颤持续时间/s
Sham组	41.60±8.29	170.00±8.72	1.16±2.59
CKD组	86.80±10.73	206.40±25.63	10.02±6.56
t	7.451^＊＊	3.007^＊	2.807^＊

组别	QT间期/ms	窦房结恢复时间/ms	房颤持续时间/s
Sham组	41.60±8.29	170.00±8.72	1.16±2.59
CKD组	86.80±10.73	206.40±25.63	10.02±6.56
t	7.451^＊＊	3.007^＊	2.807^＊

组别	0周	4周	8周	15周
SHAM组	3.96±0.12	3.95±0.36	3.96±0.34	4.00±0.40
CKD组	3.98±0.35	4.63±0.16	4.67±0.38	4.81±0.10
t	0.131	3.909^＊＊	3.128^＊	4.381^＊＊