| Autor: |
Estrela GR; Department of Clinical and Experimental Oncology, Discipline of Hematology and Hematotherapy, Federal University of São Paulo, São Paulo 04037002, Brazil.; Department of Medicine, Discipline of Nephrology, Federal University of São Paulo, São Paulo 04039032, Brazil., Arruda AC; Department of Medicine, Discipline of Nephrology, Federal University of São Paulo, São Paulo 04039032, Brazil.; Department of Biophysics, Federal University of São Paulo, São Paulo 04039032, Brazil., Torquato HFV; Department of Biochemistry, Federal University of São Paulo, São Paulo 04044020, Brazil.; Faculty of Pharmacy, University Center Braz Cubas, Mogi das Cruzes 08773380, Brazil., Freitas-Lima LC; Department of Biophysics, Federal University of São Paulo, São Paulo 04039032, Brazil., Perilhão MS; Department of Medicine, Discipline of Nephrology, Federal University of São Paulo, São Paulo 04039032, Brazil.; Department of Biophysics, Federal University of São Paulo, São Paulo 04039032, Brazil., Wasinski F; Department of Physiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508000, Brazil., Budu A; Department of Biophysics, Federal University of São Paulo, São Paulo 04039032, Brazil., Fock RA; Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508000, Brazil., Paredes-Gamero EJ; Department of Biochemistry, Federal University of São Paulo, São Paulo 04044020, Brazil.; Faculty of Pharmaceutical, Sciences, Food and Nutrition, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul 79070900, Brazil., Araujo RC; Department of Medicine, Discipline of Nephrology, Federal University of São Paulo, São Paulo 04039032, Brazil.; Department of Biophysics, Federal University of São Paulo, São Paulo 04039032, Brazil. |
| Abstrakt: |
Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug; we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha ( HIF-2α ) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2α and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice. |
