Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

慢性肾脏病 （CKD） 对心脏有不利影响。肾脏和心脏之间的潜在机制和相互作用仍然不清楚。我们使用单侧输尿管阻塞 （UUO） 诱导的小鼠 CKD 临床前模型检查了心脏效应。超声心动图、心脏组织病理学、ANP 和 BNP 的心肌 mRNA 表达、纤维化 （TGF-β、α-SMA 和胶原蛋白 I） 和表观遗传 （组蛋白脱乙酰酶，即 HDAC3 、 HDAC4 和 HDAC6） 蛋白的范围，以及心肌炎症反应。UUO 手术后 6 周，我们观察到左心室壁厚度受损和心脏肥大、相关纤维化积累和心脏炎症蛋白的迹象。此外，我们观察到心脏中表观遗传蛋白的扰动，尤其是 HDAC3 、 HDAC4 和 HDAC6。使用ricolinostat （RIC） 对 HDAC6 进行药理学抑制可减轻心脏损伤并改善左心室壁厚度。RIC 治疗显着恢复了血清心脏损伤标志物，即肌酸激酶-MB 和乳酸脱氢酶 （LDH） 活性、ANP 和 BNP mRNA 表达以及心脏组织学变化。RIC 治疗组心肌纤维化蛋白、磷酸化 NF-κB （p65） 和促炎细胞因子 （TNF-α 、 IL-18 和 IL-1β） 的范围显著降低。进一步的发现揭示了 CKD 诱导的心脏中 CD3 、 CD8a 、 CD11c 和 F4/80 阳性炎症细胞的浸润。用 RIC 治疗大大减少了这些炎症细胞的心肌浸润。 从这些发现来看，我们认为 CKD 诱导的心肌 HDAC6 扰动对心脏有恶化作用，抑制 HDAC6 可能是缓解 CKD 诱导的心肌重塑的一种有前途的方法。