Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (− 62%) in SHRob as compared with controls. RDN reduced RAGE expression (− 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (− 57% CML and − 51% HMGB1) with reduced pro-inflammatory NFkB activation (− 96%), IL-6 production (− 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (− 33%), collagen type I content (− 72%), accompanied by reduced LA myocyte hypertrophy (− 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.

心房颤动 (AF) 在患有代谢综合征的高血压患者中非常普遍，并且与炎症和交感肾上腺素能系统的激活有关。多配体高级糖基化终末产物受体 (RAGE) 可激活炎症相关组织重塑，并受交感神经系统调节。它的对应物，可溶性 RAGE (sRAGE)，作为具有保护特性的抗炎诱饵受体。我们研究了肾去神经支配 (RDN) 对交感神经调节对代谢综合征中心房重构、RAGE/sRAGE 和 RAGE 配体的影响。与瘦型自发性高血压大鼠 (SHR) 和血压正常的非肥胖对照大鼠相比，在患有代谢综合征的自发性高血压肥胖大鼠 (SHRob) 中进行 RDN。通过遥测技术测量血压和心率。RDN 后 12 周处死动物。通过组织学分析和胶原蛋白类型评估左心房 (LA) 和右心房 (RA) 重塑。通过心房神经纤维的酪氨酸羟化酶染色测量交感神经支配，通过蛋白质印迹和免疫荧光染色分析 RAGE/sRAGE、RAGE 配体、细胞因子表达和炎症浸润。SHRob 的 LA 交感神经纤维密度 (+44%) 高于对照组，而在 RDN 后降低（-64% 对比 SHRob）。与对照组相比，SHRob 中的 RAGE 增加 (+718%) 并且 sRAGE 减少 (− 62%)。RDN 降低了 RAGE 表达（− 61% 与 SHRob 相比），显着增加 sRAGE 水平 (+162%) 并诱导 SHRob 中 RAGE 配体水平显着降低（- 57% CML 和 - 51% HMGB1），促炎性 NFkB 激活减少（- 96%），IL-6 产生（- 55%) 并减少炎症浸润。这导致心房纤维化 (− 33%) 和 I 型胶原蛋白含量 (− 72%) 减少，同时 LA 肌细胞肥大减少 (− 21%)。对 H9C2 心肌细胞的转染实验表明，RAGE 通过影响 I 型胶原蛋白的细胞生成直接参与纤维化形成。总之，RDN 对肾交感神经活动的抑制通过减少心房交感神经支配和调节 RAGE/ sRAGE 平衡并减少促炎和促纤维化 RAGE 配体，