The protective effect of bergamot polyphenolic fraction on reno-cardiac damage induced by DOCA-salt and unilateral renal artery ligation in rats

Abstract Funding Acknowledgements None. The complex pathological interactions between renal and cardiovascular systems represent a real global epidemic and renovascular hypertension remains among the most prevalent, but also potentially reversible, risk factor for numerous reno-cardiac diseases in humans and pets. Here, we investigated the anti-inflammatory and reno-cardiac protective effects of a polyphenol-rich fraction of citrus bergamot (BPF) in an experimental model of hypertension induced by unilateral renal artery ligation (RAL). Adult male Wistar rats underwent unilateral renal artery ligation and treatment with 20 mg/kg deoxycorticosterone acetate (DOCA), twice a week for a period of 4 weeks, and 1% sodium chloride water. A subgroup of hypertensive rats received 100 mg/kg/day of BPF for 28 days, by gavage. Another group of animals was treated with a sub-cutaneous injection of vehicle (CTRL). RAL DOCA-Salt rats showed a significant increase in mean arterial blood pressure (MAP; p0.05 vs CTRL) which strongly increased the resistive index (RI; p0.05 vs CTRL) of contralateral renal artery flow and kidney volume after 4 weeks (p0.001 vs CTRL). Renal dysfunction also led to a dysfunction of cardiac tissue strain associated with overt dyssynchrony in cardiac wall motion, as shown by the increased time-to-peak (T2P; p0.05) and the decreased whole peak capacity (Pk; p0.01) in displacement and strain rate (p0.05) in longitudinal motion. The hearts of RAL DOCA-Salt rats showed a larger time delay between the fastest and the lowest region (Maximum Opposite Wall Delay-MOWD) (p0.05 in displacement and p0.01 in strain rate vs CTRL). A significant increase in the levels of the circulating pro-inflammatory cytokines and chemokines (p0.05 for IL-12(40), p0.01 for GM-CSF, KC, IL-13, and TNF- α) and in the NGAL expression of the ligated kidney (p0.001) was observed.This pathological condition was prevented by BPF treatment, by reducing the increase of blood pressure in RAL DOCA-Salt rats (p0.05) and exerting a protective effect on the volume of the contralateral kidney (p0.01). BPF ameliorates cardiac tissue strain dysfunction by increasing Pk in displacement (p0.01) and reducing the T2P in strain rate motion (p0.05). These effects significantly improve MOWD (p0.05) preventing the overt dyssynchrony in cardiac wall motion. The reno-cardiac protective effect of BPF was associated with a significant reduction in serum level of the pro-inflammatory cytokines and chemokines (p0.05 for KC and IL-12(40), p0.01 for GM-CSF, IL-13, and TNF- α)restoring physiological levels of NGAL (p0.05) protein of the tethered kidney. In conclusion, the present results show that BPF promotes an efficient renovascular protection preventing the progression of inflammation and reno-cardiac damage, suggesting the potential clinical and veterinary role of dietary supplementation with the polyphenol-rich fraction of citrus bergamot in counteracting hypertension-induced reno-cardiac syndrome.