P310Cardiotrophin-1 is involved in cardiovascular and renal fibrosis and dysfunction

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Abstract

Background

Cardiotrophin-1 (CT-1), a cytokine belonging to the interleukin-6 family, is increased in hypertension and in heart failure. However, the precise role of CT-1 on cardiac, vascular and renal function, morphology and remodelling is unknown.

Methods and results

CT-1 (20 μg/Kg/day) or vehicle were administrated to Wistar rats for 6 weeks. Left ventricular (LV) dimensions, cardiac and vascular function were analysed using M-mode echocardiography, Doppler assessment, echotracking device and a novel scanning acoustic microscopy (SAM) method. Cardiovascular and renal morphology and fibrosis were measured by immunohistochemistry, RT-PCR and Western Blot. Kidney functional properties were assessed by serum creatinine and neutrophile gelatinase-associated lipocalin (NGAL) and microalbuminuria/creatininuria ratio. Without alterations in blood pressure levels, CT-1 treatment increased LV volumes, reduced fractional shortening and ejection fraction, and induced LV dilatation and myocardial fibrosis. Cardiovascular coupling assessed by the ratio end systolic volume on stroke volume was impaired in CT-1 treated rats. In CT-1-treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward and acoustic wavespeed was increased, indicating increased arterial stiffness. Vascular media thickness and collagen content were increased by CT-1 treatment. CT-1-treated rats presented unaltered serum creatinine concentrations but increased urinary and serum NGAL and albumin-creatinine ratio as compared to controls. This paralleled a tubulo-interstitial fibrosis accompanied by renal epithelial-mesenchymal transition.

Conclusions

CT-1 is a new potent fibrotic agent in heart, vessels and kidney that facilitates cardiovascular-renal dysfunction independently from blood pressure. Thus, CT-1 could be a new therapeutic target in the cardiorenal syndrome.

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