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.
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Giovana Seno
authors.initials: GS
authors.lastname: Di Marco
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Kentrup
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grabner
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: Ansel Philip
authors.initials: AP
authors.lastname: Amaral
authors.affiliation: Centre for Laboratory Medicine, University Hospital Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Fobker
authors.affiliation: Department of Cardiovascular Medicine, Division of Cardiology, University Hospital Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Brand
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D006352:Heart Ventricles / Q000000981:diagnostic imaging* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
chemical_list: C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor
keywords: CKD; FGF receptor; FGF23; echocardiography; left ventricular hypertrophy