Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.
Cell Mol Biol (Noisy-le-grand). 2023 May 31;69(5):197-206. doi: 10.14715/cmb/2023.69.5.31.
Oxidative stress has been shown to cause an alteration of intracellular signaling in adipocytes that may lead to various comorbidities of obesity and cardiovascular complications. Evidence suggests that dysregulation of Na, K-ATPase signaling can contribute to systemic inflammation and redox signaling that leads to various metabolic disturbances. Hence the present study aims to explore the specific role of adipocyte Na, K-ATPase signaling in the amelioration of pathophysiological alterations of experimental uremic cardiomyopathy. Experimental uremic cardiomyopathy was induced by partial nephrectomy (PNx), and adipocyte-specific expression of NaKtide, a peptide that inhibits Na, K-ATPase signaling, was achieved using a lentivirus construct with NaKtide expression driven by an adiponectin promoter. Cardiomyopathy and anemia induced in partial nephrectomy mice were accompanied by an altered molecular phenotype of adipocytes, increased systemic inflammatory cytokines and oxidant stress within 4 weeks. These changes were significantly worsened by the addition of a Western diet (enriched in fat and fructose contents) but were prevented with specific expression of NaKtide in adipocytes. The skeletal muscle-specific expression of NaKtide did not ameliorate the disease phenotype. Adipocyte dysfunction and uremic cardiomyopathy developed in PNx mice, both were significantly ameliorated by the adipocyte-specific expression of NaKtide. These findings suggest that oxidative milieu in the adipocyte has a pivotal role in the development and progression of uremic cardiomyopathy in mice subjected to partial nephrectomy. If confirmed in humans, this may be a lead for future research to explore novel therapeutic targets in chronic renal failure.
氧化应激已被证明会导致脂肪细胞内信号转导发生改变，从而导致肥胖的各种合并症和心血管并发症。有证据表明，Na+，K+-ATP 酶信号转导的失调可能导致全身炎症和氧化还原信号转导，从而导致各种代谢紊乱。因此，本研究旨在探讨脂肪细胞 Na+，K+-ATP 酶信号转导在改善实验性尿毒症性心肌病的病理生理改变中的特定作用。通过部分肾切除术（PNx）诱导实验性尿毒症性心肌病，使用带有脂联素启动子驱动 NaKtide 表达的慢病毒构建体实现脂肪细胞特异性表达 NaKtide，NaKtide 是一种抑制 Na+，K+-ATP 酶信号转导的肽。部分肾切除小鼠诱导的心肌病和贫血伴随着脂肪细胞分子表型的改变、全身性炎症细胞因子和氧化应激增加，这在 4 周内发生。这些变化在添加富含脂肪和果糖的西方饮食时明显恶化，但通过脂肪细胞特异性表达 NaKtide 可以预防。NaKtide 的骨骼肌特异性表达并不能改善疾病表型。PNx 小鼠发生脂肪细胞功能障碍和尿毒症性心肌病，脂肪细胞特异性表达 NaKtide 可显著改善这些疾病表型。这些发现表明，脂肪细胞中的氧化环境在部分肾切除小鼠尿毒症性心肌病的发生和进展中起着关键作用。如果在人类中得到证实，这可能是未来研究探索慢性肾衰竭新治疗靶点的一个线索。
