Cardiotrophin 1 is involved in cardiac, vascular, and renal fibrosis and dysfunction.
Cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family, is increased in hypertension and in heart failure. We aimed to study the precise role of CT-1 on cardiac, vascular, and renal function; morphology; and remodeling in early stages without hypertension. CT-1 (20 μg/kg per day) or vehicle was administrated to Wistar rats for 6 weeks. Cardiac and vascular functions were analyzed in vivo using M-mode echocardiography, Doppler, and echo tracking device and ex vivo using a scanning acoustic microscopy method. Cardiovascular and renal histomorphology were measured by immunohistochemistry, RT-PCR, and Western blot. Kidney functional properties were assessed by serum creatinine and neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. Without alterations in blood pressure levels, CT-1 treatment increased left ventricular volumes, reduced fractional shortening and ejection fraction, and induced myocardial dilatation and myocardial fibrosis. In the carotid artery of CT-1-treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward, and the acoustic speed of sound in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen, and fibronectin content were increased by CT-1 treatment. CT-1-treated rats presented unaltered serum creatinine concentrations but increased urinary and serum neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. This paralleled a glomerular and tubulointerstitial fibrosis accompanied by renal epithelial-mesenchymal transition. CT-1 is a new potent fibrotic agent in heart, vessels, and kidney able to induce cardiovascular-renal dysfunction independent from blood pressure. Thus, CT-1 could be a new target simultaneously integrating alterations of heart, vessels, and kidney in early stages of heart failure.
Institut National de la Santé et de la Recherche Médicale U961, Faculty of Medicine, Vandoeuvre-lès-Nancy, France. nlopand@alumni.unav.es
Natalia
N
López-Andrés
Amélie
A
Rousseau
Riaz
R
Akhtar
Laurent
L
Calvier
Carmen
C
Iñigo
Carlos
C
Labat
Xuegen
X
Zhao
Kennedy
K
Cruickshank
Javier
J
Díez
Faiez
F
Zannad
Patrick
P
Lacolley
Patrick
P
Rossignol
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology*; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D014463:Ultrasonography; D059289:Vascular Stiffness / Q000187:drug effects / Q000502:physiology
D016207:Cytokines; C092073:cardiotrophin 1; D003404:Creatinine