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Cardiotrophin 1 is involved in cardiac, vascular, and renal fibrosis and dysfunction
Natalia López-Andrés1, Amélie Rousseau, Riaz Akhtar
1Institut National de la Santé et de la Recherche Médicale U961, Faculty of Medicine, Vandoeuvre-lès-Nancy, France. nlopand@alumni.unav.es
Insights
Cardiotrophin 1 (CT-1) causes heart, blood vessel, and kidney damage without raising blood pressure. This cytokine acts as a potent fibrotic agent, suggesting it could be a therapeutic target for early cardiovascular-renal dysfunction.
Area of Science:
- Cardiovascular Biology
- Renal Physiology
- Cytokine Signaling
Background:
- Cardiotrophin 1 (CT-1), an interleukin 6 family cytokine, is elevated in hypertension and heart failure.
- The specific role of CT-1 in early-stage cardiovascular and renal changes, independent of hypertension, requires elucidation.
Purpose of the Study:
- To investigate the precise effects of CT-1 on cardiac, vascular, and renal function, morphology, and remodeling in the absence of hypertension.
- To determine if CT-1 induces cardiovascular-renal dysfunction and fibrosis independently of blood pressure alterations.
Main Methods:
- Administration of CT-1 or vehicle to Wistar rats for 6 weeks.
- In vivo and ex vivo analysis of cardiac and vascular function (echocardiography, Doppler, echo tracking, scanning acoustic microscopy).
- Histomorphological assessment of cardiovascular and renal tissues (immunohistochemistry, RT-PCR, Western blot) and kidney function markers (serum creatinine, NGAL, albuminuria/creatininuria ratio).
Main Results:
- CT-1 treatment induced cardiac dilatation, myocardial fibrosis, reduced ejection fraction, and increased left ventricular volumes without altering blood pressure.
- Arterial stiffness increased, evidenced by leftward shift in the stress-strain curve and augmented aortic acoustic speed of sound, with increased vascular media thickness, collagen, and fibronectin.
- Renal fibrosis, glomerular and tubulointerstitial changes, and epithelial-mesenchymal transition were observed, alongside elevated urinary and serum NGAL and albuminuria/creatininuria ratio, despite normal serum creatinine.
Conclusions:
- CT-1 acts as a potent fibrotic agent in the heart, vasculature, and kidneys.
- CT-1 induces cardiovascular-renal dysfunction independently of blood pressure, suggesting a role in early-stage heart failure.
- CT-1 represents a potential therapeutic target for simultaneous intervention in heart, vessel, and kidney alterations.
Abstract:
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.
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