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Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD.

Publication ,  Journal Article
Di Marco, GS; Reuter, S; Kentrup, D; Grabner, A; Amaral, AP; Fobker, M; Stypmann, J; Pavenstädt, H; Wolf, M; Faul, C; Brand, M
Published in: Nephrol Dial Transplant
November 2014

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.

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Published In

Nephrol Dial Transplant

DOI

EISSN

1460-2385

Publication Date

November 2014

Volume

29

Issue

11

Start / End Page

2028 / 2035

Location

England

Related Subject Headings

  • Ventricular Function, Left
  • Urology & Nephrology
  • Renal Insufficiency, Chronic
  • Receptors, Fibroblast Growth Factor
  • Rats, Sprague-Dawley
  • Rats
  • Pyrimidines
  • Male
  • Injections, Intraperitoneal
  • Hypertrophy, Left Ventricular
 

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Di Marco, G. S., Reuter, S., Kentrup, D., Grabner, A., Amaral, A. P., Fobker, M., … Brand, M. (2014). Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. Nephrol Dial Transplant, 29(11), 2028–2035. https://doi.org/10.1093/ndt/gfu190
Di Marco, Giovana Seno, Stefan Reuter, Dominik Kentrup, Alexander Grabner, Ansel Philip Amaral, Manfred Fobker, Jörg Stypmann, et al. “Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD.Nephrol Dial Transplant 29, no. 11 (November 2014): 2028–35. https://doi.org/10.1093/ndt/gfu190.
Di Marco GS, Reuter S, Kentrup D, Grabner A, Amaral AP, Fobker M, et al. Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. Nephrol Dial Transplant. 2014 Nov;29(11):2028–35.
Di Marco, Giovana Seno, et al. “Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD.Nephrol Dial Transplant, vol. 29, no. 11, Nov. 2014, pp. 2028–35. Pubmed, doi:10.1093/ndt/gfu190.
Di Marco GS, Reuter S, Kentrup D, Grabner A, Amaral AP, Fobker M, Stypmann J, Pavenstädt H, Wolf M, Faul C, Brand M. Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. Nephrol Dial Transplant. 2014 Nov;29(11):2028–2035.
Journal cover image

Published In

Nephrol Dial Transplant

DOI

EISSN

1460-2385

Publication Date

November 2014

Volume

29

Issue

11

Start / End Page

2028 / 2035

Location

England

Related Subject Headings

  • Ventricular Function, Left
  • Urology & Nephrology
  • Renal Insufficiency, Chronic
  • Receptors, Fibroblast Growth Factor
  • Rats, Sprague-Dawley
  • Rats
  • Pyrimidines
  • Male
  • Injections, Intraperitoneal
  • Hypertrophy, Left Ventricular