The active ingredient in the nuphar lutea plant, 6,6 ' : dihydroxythiobinupharidine (dtbn) ameliorates kidney fibrosis, inflammation and anemia in a mouse model of chronic kidney disease (ckd)

Abstract BACKGROUND AND AIMS EPO resistance and iron deficiency in CKD-related anemia are associated with an increase in inflammatory cytokines associated with the innate immune response, such as IL-6, IL-1 and TNF-α. Recently (Bandach et al. Sci Reports 2021) we reported that kidney fibrosis and anemia of CKD can be worsened or relieved when IL1 effects are enhanced or inhibited respectively. The Water lily (Nuphar lutea) plant has been widely used as a traditional remedy for the treatment of rheumatism, scars, pain and more. Gopas, Golan-Goldhirsh et al. (Cancer Biology Therapy 2009) extracted an active ingredient from the family of nupharidines: 6,6′-Dihydroxythiobinupharidine (DTBN), which showed anti-inflammatory properties, mainly through the inhibition of NF-κB. The purpose of this study was to test the effects of DTBN in a mouse model of CKD-associated anemia. METHOD 8 weeks old male C57BL/6 mice were divided into three groups: control, CKD (induced by adenine diet) and CKD-DTBN. CKD groups were injected with saline-DMSO or 30 µg DTBN, every 2 days and sacrificed after 3 weeks from dietary intervention. RESULTS Serum urea and kidney TGFβ mRNA were significantly decreased in CKD- DTBN versus CKD. Kidney histology in CKD mice showed macrophage infiltration and renal fibrosis, which was ameliorated in CKD-DTBN. A significant improvement in inflammation indices (blood lymphocytes, kidney and liver IL-6 and p-STAT3, liver CRP), as well as kidney immunoreactive NF-κB and F4\80, which were increased in CKD, were decreased in CKD-DTBN. CKD anemia indices (hemoglobin, hematocrit and red blood cell (RBC) count) significantly improved in CKD-DTBN. Kidney HIF-2α and EPO mRNA were significantly decreased in both uremic groups, but was unchanged in CKD- DTBN versus CKD. However, serum iron and transferrin saturation significantly increased in CKD-DTBN versus CKD. CONCLUSION Uremic mice treated with DTBN show improvement in kidney fibrosis, inflammation and anemia indices. Thus, DTBN may be a novel therapeutic alternative for CKD and its complications.