Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
Am J Physiol Renal Physiol. 2021 Oct 1;321(4):F411-F423. doi: 10.1152/ajprenal.00158.2021. Epub 2021 Aug 16.
Patients with chronic kidney disease (CKD) have a high cardiovascular mortality. CKD and heart failure (HF) coexist in up to 50% of patients, and both associate with inflammation. We aimed to define the cardiac phenotype of a novel swine model of CKD and test the hypothesis that inflammation of renal origin propels the development of precursors of HF in CKD. CKD was induced in 14 pigs, which were followed for 14 wk. Renal (multidetector computed tomography) and cardiac (echocardiography) hemodynamics were quantified before and 8 wk after single intrarenal administration of placebo or a biopolymer-fused peptide inhibitor of NF-κB that blocks NF-κB activity and decreases inflammatory activity (SynB1-ELP-p50i). Blood was collected to quantify cytokines (TNF-α, monocyte chemoattractant protein-1, and interleukins), markers of inflammation (C-reactive protein), and biomarkers of HF (atrial and brain natriuretic peptides). Pigs were then euthanized, and kidneys and hearts were studied ex vivo. Normal pigs were used as time-matched controls. Renal dysfunction in CKD was accompanied by cardiac hypertrophy and fibrosis, diastolic dysfunction, increased renal and cardiac expression of TNF-α, monocyte chemoattractant protein-1, and interleukins, canonical and noncanonical mediators of NF-κB signaling, circulating inflammatory factors, and biomarkers of HF. Notably, most of these changes were improved after intrarenal SynB1-SynB1-ELP-p50i, although cardiac inflammatory signaling remained unaltered. The translational traits of this model support its use as a platform to test novel technologies to protect the kidney and heart in CKD. A targeted inhibition of renal NF-κB signaling improves renal and cardiac function, suggesting an inflammatory renal-cardio axis underlying early HF pathophysiology in CKD. Chronic kidney disease (CKD) is a progressive disorder with high cardiovascular morbidity and mortality. This work supports the role of inflammatory cytokines of renal origin in renal-cardio pathophysiology in CKD and that the heart may be a target. Furthermore, it supports the feasibility of a new strategy in a translational fashion, using targeted inhibition of renal NF-κB signaling to offset the development of cardiac injury in CKD.
患有慢性肾病 (CKD) 的患者心血管死亡率较高。高达 50%的 CKD 患者同时患有心力衰竭 (HF)，且两者均与炎症相关。本研究旨在确定一种新型 CKD 猪模型的心脏表型，并验证源自肾脏的炎症会促进 CKD 中 HF 前体发展的假说。14 头猪被诱导发生 CKD，并随访 14 周。在单次肾内给予安慰剂或一种融合了 NF-κB 肽抑制剂的生物聚合物 (SynB1-ELP-p50i，可阻断 NF-κB 活性并降低炎症活性) 之前和 8 周后，对肾脏 (多排螺旋 CT) 和心脏 (超声心动图) 血流动力学进行量化。采集血液以量化细胞因子 (TNF-α、单核细胞趋化蛋白-1 和白细胞介素)、炎症标志物 (C 反应蛋白) 和 HF 标志物 (心房利钠肽和脑利钠肽)。然后处死猪，对肾脏和心脏进行离体研究。正常猪作为时间匹配的对照。CKD 时肾功能不全伴有心脏肥大和纤维化、舒张功能障碍、肾脏和心脏 TNF-α、单核细胞趋化蛋白-1 和白细胞介素表达增加、NF-κB 信号的经典和非经典介质、循环炎症因子和 HF 标志物增加。值得注意的是，虽然心脏炎症信号仍未改变，但肾内给予 SynB1-ELP-p50i 后，大多数这些变化都得到了改善。该模型的转化特征支持其作为一种平台，用于测试保护 CKD 中肾脏和心脏的新技术。肾脏 NF-κB 信号的靶向抑制可改善肾脏和心脏功能，提示 CKD 中早期 HF 病理生理学的基础可能是炎症性肾-心轴。慢性肾病 (CKD) 是一种进展性疾病，具有较高的心血管发病率和死亡率。本研究支持源自肾脏的炎症细胞因子在 CKD 肾-心病理生理学中的作用，以及心脏可能是一个靶点。此外，它以转化的方式支持一种新策略的可行性，即使用肾脏 NF-κB 信号的靶向抑制来抵消 CKD 中心脏损伤的发展。
