Oxidative Stress and Induction of Heme Oxygenase-1 in the Kidney in Sickle Cell Disease

• Published in: The American journal of pathology Vol. 158; no. 3; pp. 893 - 903
• Main Authors: Nath, Karl A., Grande, Joseph P., Haggard, Jill J., Croatt, Anthony J., Katusic, Zvonimir S., Solovey, Anna, Hebbel, Robert P.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.03.2001; ASIP; American Society for Investigative Pathology
• Subjects: Anemia, Sickle Cell - blood; Anemia, Sickle Cell - enzymology; Anemia, Sickle Cell - pathology; Anemias. Hemoglobinopathies; Animals; Biological and medical sciences; Buthionine Sulfoximine - pharmacology; Creatinine - blood; Diseases of red blood cells; Endothelium, Vascular - enzymology; Enzyme Inhibitors - pharmacology; Erythrocytes - pathology; Glutathione - biosynthesis; Hematologic and hematopoietic diseases; Heme - metabolism; Heme Oxygenase (Decyclizing) - biosynthesis; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase-1; Humans; Kidney - blood supply; Kidney - enzymology; Kidney - pathology; Lipid Peroxidation; Medical sciences; Membrane Proteins; Mice; Mice, Transgenic; Oxidative Stress; Regular; Transcriptional Activation; Immunohistochemistry; Animal model; Oxidative stress; Sickle cell anemia; Pathogenesis; Transgenic animal; Hemopathy; Hemolytic anemia; Kidney disease; Human; Hemoglobinopathy; Urinary system disease; Biochemical analysis; Enzyme; Rodentia; Heme oxygenase (decyclizing); Genetic disease; Pathology; Vertebrata; Chronic; Mammalia; Nephropathy; Mouse; Animal; Oxidoreductases; Molecular biology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)64037-0

Chronic nephropathy is a recognized complication of sickle cell disease. Using a transgenic sickle mouse, we examined whether oxidative stress occurs in the sickle kidney, the origins and functional significance of such oxidant stress, and the expression of the oxidant-inducible, potentially protective gene, heme oxygenase-1 (HO-1); we also examined the expression of HO-1 in the kidney and in circulating endothelial cells in sickle patients. We demonstrate that this transgenic sickle mouse exhibits renal enlargement, medullary congestion, and a reduced plasma creatinine concentration. Oxidative stress is present in the kidney as indicated by increased amounts of lipid peroxidation; heme content is markedly increased in the kidney. Exacerbation of oxidative stress by inhibiting glutathione synthesis with buthionine-sulfoximine dramatically increased red blood cell sickling in the sickle kidney: in buthionine-sulfoximine-treated sickle mice, red blood cell sickling extended from the medulla into the cortical capillaries and glomeruli. HO activity is increased in the sickle mouse kidney, and is due to induction of HO-1. In the human sickle kidney, HO-1 is induced in renal tubules, interstitial cells, and in the vasculature. Expression of HO-1 is increased in circulating endothelial cells in patients with sickle cell disease. These results provide the novel demonstration that oxidative stress occurs in the sickle kidney, and that acute exacerbation of oxidative stress in the sickle mouse precipitates acute vaso-occlusive disease. Additionally, the oxidant-inducible, heme-degrading enzyme, HO-1, is induced regionally in the murine and human sickle kidney, and systemically, in circulating endothelial cells in sickle patients.