Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833401, Taiwan, ROC; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan, ROC; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan, ROC.
The First Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.
Biomed Pharmacother. 2024 Nov;180:117567. doi: 10.1016/j.biopha.2024.117567. Epub 2024 Oct 18.
This study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS).
An in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p<0.001). Additionally, these two signaling pathways further significantly upregulated the hypoxia-induced factor (HIF)-1α which, in turn, significantly upregulated Nrf2/ARE (HO-1/NQO-1) and angiogenesis/cell-growth factors (EPO/SDF-1α/VEGF/FGF/IGF-2) and downregulated hypoxia-inducible factor prolyl-4-hydroxylase-1 (all p<0.001). Adult-male SD rats were categorized into Groups 1 (sham-operated control)/2 (CRS)/3 (CRS+ROX)/4 (CRS+DAPA)/5 (CRS+ROX+DAPA). By Day 60 after rodent CRS induction, the levels of BUN/creatinine and the ratio of urine protein to creatinine were lowest in Group 1, highest in Group 2, and significantly lower in Group 5 than in Groups 3 and 4; however, they were similar in the latter two groups, whereas the left-ventricular-ejection-fraction exhibited the opposite trend of creatinine among the groups (all p<0.0001). The protein expression levels of cell-survival (p-PI3K/p-Akt-p-mTOR)/cell-stress (p-JNK/p-p38/p-ERK1/2)/Nrf2-ARE (HO-1/NQO-1/SIRT1/SIRT3) signaling factors and angiogenesis factors (HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO) significantly and progressively increased from Groups 1-5 (all p<0.0001).
Combined DAPA-ROX therapy has a synergistic effect on protecting heart and kidney functions against CRS-induced damage in rodents.
本研究旨在测试达格列净（DAPA）和罗沙司他（ROX）联合治疗是否优于单一疗法，在伴有心肾综合征（CRS）的大鼠中保护心肾功能。
一项体外研究表明，ROX-DAPA 联合治疗可显著激活细胞存活（PI3K/Akt/mTOR）/细胞应激（ERK1/2、JNK/p-38）信号（均 p<0.001）。此外，这两条信号通路进一步显著上调缺氧诱导因子（HIF）-1α，继而显著上调 Nrf2/ARE（HO-1/NQO-1）和血管生成/细胞生长因子（EPO/SDF-1α/VEGF/FGF/IGF-2），并下调缺氧诱导因子脯氨酰-4-羟化酶-1（均 p<0.001）。成年雄性 SD 大鼠分为 1 组（假手术对照）/2 组（CRS）/3 组（CRS+ROX）/4 组（CRS+DAPA）/5 组（CRS+ROX+DAPA）。在诱导大鼠 CRS 后 60 天，与 3 组和 4 组相比，1 组的 BUN/肌酐水平和尿蛋白与肌酐比值最低，2 组最高，但后两组间相似，而左心室射血分数在各组间呈肌酐的相反趋势（均 p<0.0001）。细胞存活（p-PI3K/p-Akt-p-mTOR）/细胞应激（p-JNK/p-p38/p-ERK1/2）/Nrf2-ARE（HO-1/NQO-1/SIRT1/SIRT3）信号因子和血管生成因子（HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO）的蛋白表达水平从 1 组到 5 组均显著且逐渐增加（均 p<0.0001）。
DAPA-ROX 联合治疗对保护 CRS 诱导的啮齿动物心肾功能损伤具有协同作用。
