Renal Sympathetic Denervation Attenuates Angiotensin ?-induced Hypertensive Cardiovascular Remodeling

Background and Objective: Over-activation of sympathetic nerve system(SNS)plays an important role in the development of hypertension and other cardiovascular diseases.Renal sympathetic denervation(RDN)represents a potential treatment option for certain patients with resistant arterial hypertension.Renin-angiotensin-aldosterone system(RAAS)disorder is also one of the factors that lead to blood pressure elevation and cardiovascular pathophysiological changes.However,the interaction between RAAS and SNS in the pathogenesis of hypertensive cardiovascular remodeling is poorly known.The present study aimed to evaluate the influence of RDN on cardiovascular inflammation and remodeling in an animal model of Angiotensin ? induced hypertensive rats.Method: 1)8-10 weeks male Sprague-Dawley rats were divided into 2 groups,including sham-operated rats and renal denervated rats.After a week of recovery,then the shamoperated and RDN groups were further randomized into 2 groups,respectively.An osmotic minipump was implanted subcutaneously with Ang ?(200 ng/kg/min)or vehicle for 14 days.Therefore,the groups were as follows: vehicle-treated sham rats(sham,n=12),vehicle-treated RDN rats(RDN,n=12),Ang ?-treated sham rats(Ang ?,n=12)and Ang ?-treated RDN rats(Ang ? + RDN,n=12).2)We firstly detected the RSNA in Ang ? and sham rats using a powerlab system.3)Blood pressure was measured invasively using telemetry devices and non-invasively using an automated tail-cuff system.4)Achievement of RDN was assessed by detecting renal norepinephrine(NE)content and the expression of tyrosin hydroxylase(TH).Transthoracic echocardiography was performed to evaluate the wall thickness and function of the left ventricular.Both acetylcholine-induced vasodilation and phenylephrine-induced vasoconstriction were evaluated using isometric force transducers.Morphological staining was used to detect the effect of RDN on cardiovascular pathological changes.Western blot was further used to evaluate the effect of RDN on the protein expression,such as collagen I and ?I,inflammatory factors,TGF-beta/smad signaling pathway as well as ERK1/2 and p38 signaling pathways.5)Radioimmunoassay was used to evaluate the levels of aldosterone in the plasma,heart and kidney.Adrenocortical carcinoma H295 R cells were cultured to futher explore the underlying mechanism of beneficial effects of RDN on cardiovascular remodeling.We detected the concentration of aldosterone in the cell supernatant after stimulated by Angiotensin ? and calcitonin gene-related peptide.Results: 1)The renal sympathetic nerve activity was significantly inhibited by two weeks of Ang ? infusion.2)Efficacy of RDN was confirmed by the reduction of renal tyrosine hydroxylase expression and renal norepinephrine levels at 2 weeks after the procedure.3)By using telemetry,bilateral RDN suppressed the blood pressure elevation and ameliorated the mesenteric vascular dysfunction induced by Ang ?.4)Ang ?-induced cardiovascular hypertrophy was significantly blunted by RDN as shown by histopathology staining and transthoracic echocardiography.5)Ang ?-induced vascular and myocardial inflammation and fibrosis was suppressed by RDN with concurrent decrease in fibronectin and collagen deposition,macrophage infiltration,and MCP-1 expression.6)Interestingly,RDN also suppressed Ang ?-induced aldosterone expression in the plasma,kidney and heart.This was associated with reduction of CGRP in heart and adrenal gland.7)Ang ? dose-dependently promoted aldosterone secretion,this effect was partly attenuated by CGRP in adrenocortical cell line,suggesting a protective role of CGRP.8)Activation of transforming growth factor-?(TGF-?)/Smad signaling pathway as well as extracellular signal-regulated kinases(ERK)1/2 and p38 pathway were inhibited by RDN especially in the heart.Conclusion: 1.Renal denervation(RDN)attenuates blood pressure elevation and mesenteric artery dysfunction in Ang ? infusion rats.2.RDN ameliorates Ang ?-induced cardiovascular inflammation,fibrosis and remodeling,which might through inhibiting the TGF-?/Smad and MAPKs sigling pathways.3.RDN inhibits aldosterone expression in the plasma,kidney and heart,which is likely to be mediated by the expression of CGRP,thus providing an insight into the beneficial effect of renal denervation on cardiovascular diseases.