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) |
|---|---|
| Pages (from-to) | 2028-2035 |
| Number of pages | 8 |
| Journal | Nephrology Dialysis Transplantation |
| Volume | 29 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2014 |
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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 journal › Article
}
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 -