Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia.
Departments of Medicine and Pharmacology, New York Medical College, Valhalla, New York.
J Am Soc Nephrol. 2020 Aug;31(8):1746-1760. doi: 10.1681/ASN.2019101070. Epub 2020 Jun 25.
Oxidative stress in adipocyte plays a central role in the pathogenesis of obesity as well as in the associated cardiovascular complications. The putative uremic toxin indoxyl sulfate induces oxidative stress and dramatically alters adipocyte phenotype . Mice that have undergone partial nephrectomy serve as an experimental model of uremic cardiomyopathy. This study examined the effects on adipocytes of administering a peptide that reduces oxidative stress to the mouse model.
A lentivirus vector introduced the peptide NaKtide with an adiponectin promoter into the mouse model of experimental uremic cardiomyopathy, intraperitoneally. Then adipocyte-specific expression of the peptide was assessed for mice fed a standard diet compared with mice fed a western diet enriched in fat and fructose.
Partial nephrectomy induced cardiomyopathy and anemia in the mice, introducing oxidant stress and an altered molecular phenotype of adipocytes that increased production of systemic inflammatory cytokines instead of accumulating lipids, within 4 weeks. Consumption of a western diet significantly worsened the adipocyte oxidant stress, but expression of NaKtide in adipocytes completely prevented the worsening. The peptide-carrying lentivirus achieved comparable expression in skeletal muscle, but did not ameliorate the disease phenotype.
Adipocyte-specific expression of NaKtide, introduced with a lentiviral vector, significantly ameliorated adipocyte dysfunction and uremic cardiomyopathy in partially nephrectomized mice. These data suggest that the redox state of adipocytes controls the development of uremic cardiomyopathy in mice subjected to partial nephrectomy. If confirmed in humans, the oxidative state of adipocytes may be a therapeutic target in chronic renal failure.
脂肪细胞中的氧化应激在肥胖的发病机制以及相关的心血管并发症中起着核心作用。假定的尿毒症毒素吲哚硫酸酯会诱导氧化应激，并显著改变脂肪细胞表型。接受部分肾切除术的小鼠可作为尿毒症性心肌病的实验模型。本研究检查了向小鼠尿毒症性心肌病模型施用一种可降低氧化应激的肽对脂肪细胞的影响。
通过腹腔内注射，将含有脂联素启动子的肽 NaKtide 的慢病毒载体引入实验性尿毒症性心肌病的小鼠模型中。然后，与食用富含脂肪和果糖的西式饮食的小鼠相比，评估了肽在食用标准饮食的小鼠中的脂肪细胞特异性表达。
部分肾切除术在 4 周内诱导小鼠发生心肌病和贫血，从而导致氧化应激和脂肪细胞分子表型改变，导致全身炎症细胞因子的产生增加，而不是脂质积累。食用西式饮食显著加重了脂肪细胞的氧化应激，但脂肪细胞中 NaKtide 的表达完全阻止了这种恶化。携带肽的慢病毒在骨骼肌中达到了相当的表达水平，但并未改善疾病表型。
用慢病毒载体引入脂肪细胞特异性表达的 NaKtide 可显著改善部分肾切除小鼠的脂肪细胞功能障碍和尿毒症性心肌病。这些数据表明，脂肪细胞的氧化还原状态控制了接受部分肾切除术的小鼠尿毒症性心肌病的发展。如果在人类中得到证实，脂肪细胞的氧化状态可能是慢性肾衰竭的治疗靶点。
