Abstract
Background: Activation of fibroblast growth factor receptor (FGFR)-dependent signalling by FGF23 may contribute to the complex pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease (CKD). Pan FGFR blockade by PD173074 prevented development of LVH in the 5/6 nephrectomy rat model of CKD, but its ability to treat and reverse established LVH is unknown. Methods: CKD was induced in rats by 5/6 nephrectomy. Two weeks later, rats began treatment with vehicle (0.9% NaCl) or PD173074, 1 mg/kg once-daily for 3 weeks. Renal function was determined by urine and blood analyses. Left ventricular (LV) structure and function were determined by echocardiography, histopathology, staining for myocardial fibrosis (Sirius-Red) and investigating cardiac gene expression profiles by real-time PCR. Results: Two weeks after inducing CKD by 5/6 nephrectomy, rats manifested higher (mean ± SEM) systolic blood pressure (208 ± 4 versus 139 ± 3 mmHg; P < 0.01), serum FGF23 levels (1023 ± 225 versus 199 ± 9 pg/mL; P < 0.01) and LV mass (292 ± 9 versus 220 ± 3 mg; P < 0.01) when compared with sham-operated animals. Thereafter, 3 weeks of treatment with PD173074 compared with vehicle did not significantly change blood pressure, kidney function or metabolic parameters, but significantly reduced LV mass (230 ± 14 versus 341 ± 33 mg; P<0.01), myocardial fibrosis (2.5 ±0.7 versus 5.4 ±0.95% staining/field; P<0.01) and cardiac expression of genes associated with pathological LVH, while significantly increasing ejection fraction (18 versus 2.5% post-treatment increase; P< 0.05). Conclusions: FGFR blockade improved cardiac structure and function in 5/6 nephrectomy rats with previously established LVH. These data support FGFR activation as a potentially modifiable, blood pressure-independent molecular mechanism of LVH in CKD.
Original language | English (US) |
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Pages (from-to) | 2028-2035 |
Number of pages | 8 |
Journal | Nephrology Dialysis Transplantation |
Volume | 29 |
Issue number | 11 |
DOIs | |
State | Published - Nov 1 2014 |
Funding
The authors thank Katrin Beul and Richard Holtmeier for their excellent technical assistance. MB and this study was supported by Stifterverband für die Deutsche Wissenschaft und der Simon-Claussen-Stiftung (Project H1405409999915626). S.R., D.K. and A.G. were supported by the Deutsche Forschungsgemeinschaft, CRC 656, Project C7.
Keywords
- CKD
- Echocardiography
- FGF receptor
- FGF23
- Left ventricular hypertrophy
ASJC Scopus subject areas
- Nephrology
- Transplantation