Combined dapagliflozin and roxadustat effectively protected heart and kidney against cardiorenal syndrome-induced damage in rodent through activation of cell stress-Nfr2/ARE signalings and stabilizing HIF-1α

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. The results of this study proved that combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy on improving outcomes in rodents with cardiorenal syndrome. The underlying mechanisms of the protective effect mainly though (1) DAPA upregulated PI3K/Akt/m-TOR signaling/MAPK family member-mediated activation of HIF-1α signaling, subsequently stimulated renal-derived fibroblasts to generate the angiogenic factors and antioxidants and (2) ROX treatment augmented the generation of HIF-1α, angiogenic factors and antioxidants by suppressing the activity of HIF-P4H. • Dapagliflozin modulated cell stress signalings through augmentation of anti-oxidants and hypoxia-induced factor (HIF)-1α. • Roxadustat stabilized the HIF-1α level and enhanced generation of angiogenesis factors. • Combined Dapagliflozin-Roxadustat offered a synergistic effect on cardiorenal protection against CRS-associated damages.