Differential gene expression in the kidney of sickle cell transgenic mice: upregulated genes.
The S+S-Antilles transgenic mouse used in this study has renal defects similar to those seen in sickle cell anemia patients: congested glomeruli, medullary fibrosis, renal enlargement, vasoocclusion, and a urine concentrating defect. We used gene expression microarrays to identify genes highly up-regulated in the kidneys of these mice and validated their expression by real-time PCR. Kidney hypoxia, as demonstrated by the presence of deoxyhemoglobin, was detected by blood oxygen dependent magnetic resonance imaging (BOLD-MRI). Some of the up-regulated genes included cytochrome P450 4a14, glutathione-S-transferase alpha-1, mitochondrial hydroxymethylglutaryl CoA synthase, cytokine inducible SH-2 containing protein, retinol dehydrogenase type III, arginase II, glycolate oxidase, Na/K ATPase, renin-1, and alkaline phosphatase 2. An increase in enzyme activity was also demonstrated for one of the up-regulated genes (arginase II). These genes can be integrated into several different pathophysiological processes: a hypoxia cascade, a replacement cascade, or an ameliorating cascade, one or all of which may explain the phenotype of this disease. We conclude that microarray technology is a powerful tool to identify genes involved in renal disease in sickle cell anemia and that the identification of various metabolic pathways may open new avenues for therapeutic interventions.
Rybicki
Anne C
AC
Department of Medicine, Division of Hematology, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Fabry
Mary E
ME
Does
Mark D
MD
Kaul
Dhananjay K
DK
Nagel
Ronald L
RL
D000755:Anemia, Sickle Cell / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002956:Citrulline / Q000097:blood; D020869:Gene Expression Profiling; D006454:Hemoglobins / Q000032:analysis; D007668:Kidney / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D009952:Ornithine / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000235:genetics*
D006454:Hemoglobins; D012333:RNA, Messenger; D002956:Citrulline; C100003:deoxyhemoglobin; D001120:Arginine; D009952:Ornithine