Abstract
We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.
Highlights
We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/ Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome
Parameter Body weight (g) Systolic blood pressure Diastolic blood pressure Heart rate Lung weight/tibia length LV weight/tibia length Spleen weight/tibia length Kidney weight/tibia length Red blood cell (× 106/μL) Hemoglobin (g/dL) Hematocrit (%) MCH MCV MCHC (g/dL) Reticulocyte (%) Reticulocyte (× 104/μL) RDW-CV (%) Platelet (× 104/μL) Creatinine Fe total iron binding capacity (TIBC) UIBC Total-billirubin Indirect-billirubin Urine volume Urine protein Urine protein/creatinine siderin into the renal proximal tubular epithelial cells caused by intravascular hemolysis, iron chelator DFX was administered by gavage to the Dahl/Salt Sensitive (Dahl/SS) rats fed with high-salt diet
This study showed that anemia in Dahl/SS rats fed with high-salt diet was caused by reduced half-life of erythrocytes in peripheral blood
Summary
We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/ Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. An oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. Reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model. Cause of anemia in CRAS has been suggested to be multifactorial It includes increased circulating plasma volume due to fluid retention[8], decreased bone marrow hematopoietic response[9], decreased erythropoietin secretion with CKD, iron absorption/use d isorder[10,11], nutrient deficiency due to decreased appetite, steroid metabolism abnormalities[12], and effects of therapeutic drugs, etc. We report the role of hemosiderin accumulation in renal damage and effect of treatment with deferasirox (DFX), an oral iron chelator
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