Prolyl hydroxylase inhibitor desidustat attenuates autoimmune hemolytic anemia in mice

• Published in: International immunopharmacology Vol. 142; no. Pt A; p. 113029
• Main Authors: Patel, Vishal J., Joharapurkar, Amit A., Kshirsagar, Samadhan G., Patel, Maulik S., Savsani, Hardikkumar H., Rakhasiya, Milan H., Dodiya, Harshad S., Jain, Mukul R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.12.2024
• Subjects: Anemia, Hemolytic, Autoimmune - drug therapy; Anemia, Hemolytic, Autoimmune - immunology; Animals; Antibody; Autoantibodies - blood; Autoantibodies - immunology; Autoimmune-hemolytic anemia; Complement system; Desidustat; Disease Models, Animal; Erythrocytes - drug effects; Erythrocytes - immunology; Iron - metabolism; Male; Mice; Oxidative Stress - drug effects; Prolyl-Hydroxylase Inhibitors - pharmacology; Prolyl-Hydroxylase Inhibitors - therapeutic use; Rats; Spleen - drug effects; Spleen - immunology; Autoimmune-hemolytic anemia; Complement system; Antibody; Desidustat
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113029

[Display omitted] •Prolyl hydroxylase inhibitor desidustat increased hemoglobin in autoimmune anemia.•Desidustat increased RBC lifespan and decreased antibody deposition on RBC.•Desidustat increased erythroid maturation (TER-119) in bone marrow.•Hypoxia-inducible factor stabilizer reduces iron in tissue and serum.•PHD inhibitor suppressed oxidative stress and serum LDH. Autoimmune hemolytic anemia (AIHA) is a heterogeneous group of diseases mediated by autoantibody directed against RBCs causing hemolysis and anemia. AIHA develops rapidly or over time, depending on the triggering factor. Desidustat is a prolyl hydroxylase inhibitor clinically used for the treatment of chronic kidney disease (CKD)-induced anemia. In this study, we investigated the effect of desidustat in preclinical model of AIHA. We used rat RBC for induction of AIHA in mice. These mice were then treated with desidustat (15 mg/kg, PO, once a day) for eight weeks. Desidustat treatment increased hemoglobin, RBC and hematocrit and decreased WBC and lymphocytes. This treatment suppressed serum LDH, oxidative stress in RBCs, antibody titer and antibody deposition on RBC surface, and increased RBC lifespan. Serum and spleen iron along with spleen mass and oxidative stress were decreased by desidustat. Bone marrow iron was increased and expression of CD71 (cell surface marker for early erythroid progenitor) and TER-119 (cell surface marker for late erythroid progenitor) in bone marrow were found to be elevated by desidustat by treatment. This treatment also suppressed deposition of membrane-bound antibody in late erythroid cells. The treatment showed reduction in total splenic cells, CD71 and TER-119 positive cells in the spleen. Thus, desidustat treatment increased erythropoiesis, early maturation of bone marrow erythroid cells having longer RBC life span due to decrease in the antibody-mediated lysis of RBCs and its progenitors leading to reduced oxidative stress. Thus, desidustat can be a good therapeutic option for treatment of AIHA.