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

Giovana Seno Di Marco, Stefan Reuter, Dominik Kentrup, Alexander Grabner, Ansel Philip Amaral, Manfred Fobker, Jörg Stypmann, Hermann Pavenstädt, Myles Wolf, Christian H Faul, Marcus Brand

Research output: Contribution to journalArticle

49 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2028-2035
Number of pages8
JournalNephrology Dialysis Transplantation
Volume29
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

Fibroblast Growth Factor Receptors
Left Ventricular Hypertrophy
Chronic Renal Insufficiency
Animal Models
Nephrectomy
Blood Pressure
Fibrosis
Staining and Labeling
Kidney
Transcriptome
Left Ventricular Function
Echocardiography
Real-Time Polymerase Chain Reaction
Urine
Gene Expression
Serum
PD 173074

Keywords

  • CKD
  • Echocardiography
  • FGF receptor
  • FGF23
  • Left ventricular hypertrophy

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. / Di Marco, Giovana Seno; Reuter, Stefan; Kentrup, Dominik; Grabner, Alexander; Amaral, Ansel Philip; Fobker, Manfred; Stypmann, Jörg; Pavenstädt, Hermann; Wolf, Myles; Faul, Christian H; Brand, Marcus.

In: Nephrology Dialysis Transplantation, Vol. 29, No. 11, 01.11.2014, p. 2028-2035.

Research output: Contribution to journalArticle

Di Marco, GS, Reuter, S, Kentrup, D, Grabner, A, Amaral, AP, Fobker, M, Stypmann, J, Pavenstädt, H, Wolf, M, Faul, CH & Brand, M 2014, 'Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD', Nephrology Dialysis Transplantation, vol. 29, no. 11, pp. 2028-2035. https://doi.org/10.1093/ndt/gfu190
Di Marco, Giovana Seno ; Reuter, Stefan ; Kentrup, Dominik ; Grabner, Alexander ; Amaral, Ansel Philip ; Fobker, Manfred ; Stypmann, Jörg ; Pavenstädt, Hermann ; Wolf, Myles ; Faul, Christian H ; Brand, Marcus. / Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. In: Nephrology Dialysis Transplantation. 2014 ; Vol. 29, No. 11. pp. 2028-2035.
@article{d49c7cce9ebe43f2808d7b49f79e2925,
title = "Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD",
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.",
keywords = "CKD, Echocardiography, FGF receptor, FGF23, Left ventricular hypertrophy",
author = "{Di Marco}, {Giovana Seno} and Stefan Reuter and Dominik Kentrup and Alexander Grabner and Amaral, {Ansel Philip} and Manfred Fobker and J{\"o}rg Stypmann and Hermann Pavenst{\"a}dt and Myles Wolf and Faul, {Christian H} and Marcus Brand",
year = "2014",
month = "11",
day = "1",
doi = "10.1093/ndt/gfu190",
language = "English (US)",
volume = "29",
pages = "2028--2035",
journal = "Nephrology Dialysis Transplantation",
issn = "0931-0509",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD

AU - Di Marco, Giovana Seno

AU - Reuter, Stefan

AU - Kentrup, Dominik

AU - Grabner, Alexander

AU - Amaral, Ansel Philip

AU - Fobker, Manfred

AU - Stypmann, Jörg

AU - Pavenstädt, Hermann

AU - Wolf, Myles

AU - Faul, Christian H

AU - Brand, Marcus

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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.

AB - 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.

KW - CKD

KW - Echocardiography

KW - FGF receptor

KW - FGF23

KW - Left ventricular hypertrophy

UR - http://www.scopus.com/inward/record.url?scp=84986563782&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84986563782&partnerID=8YFLogxK

U2 - 10.1093/ndt/gfu190

DO - 10.1093/ndt/gfu190

M3 - Article

C2 - 24875663

AN - SCOPUS:84986563782

VL - 29

SP - 2028

EP - 2035

JO - Nephrology Dialysis Transplantation

JF - Nephrology Dialysis Transplantation

SN - 0931-0509

IS - 11

ER -