title: Pathophysiology of a sickle cell trait mouse model: human alpha(beta)(S) transgenes with one mouse beta-globin allele.
abstract: As a potential model for sickle cell trait (AS), we examined mice containing one normal mouse beta-globin allele in combination with a human hemoglobin S (h(alpha)beta(S)) transgene (m(beta)/hS). The mice segregated into two subpopulations containing low and high proportions of hemoglobin S (m(beta)/hS1 and m(beta)/hS2, respectively) that was associated with one or two human h(alpha)beta(S) transgenes. We noted striking kidney pathology (cortical cysts, hyperplastic tubules, and glomerulonephritis), increasing with age and with greater severity in m(beta)/hS1. mBeta/hS2 animals were largely tolerant to 5% O(2) for 1 h, whereas 80% of m(beta)/hS1 mice died, exhibiting acute sequestration of erythrocytes in spleen, liver, and heart. These pathologies appear to result from a decreased oxygen affinity of the hybrid (human alpha/mouse beta) hemoglobins with a mild beta-thalassemia phenotype. Thus, these mouse models of sickle trait seem to manifest their renal pathology and sensitivity to hypoxia by mechanisms related to low tissue oxygen delivery and are different from the human syndrome. Analyses of parameters such as P(50), red cell indices, and genetic background are necessary in establishing potential relevance of any mouse model of the sickle cell syndromes.
authors.affiliation: Laboratory of Chemical Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1822, USA. cnoguchi@helix.nih.gov
authors.forename: C T
authors.initials: CT
authors.lastname: Noguchi
authors.forename: M
authors.initials: M
authors.lastname: Gladwin
authors.forename: B
authors.initials: B
authors.lastname: Diwan
authors.forename: P
authors.initials: P
authors.lastname: Merciris
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.forename: G
authors.initials: G
authors.lastname: Buzard
authors.forename: A
authors.initials: A
authors.lastname: Fitzhugh
authors.forename: L K
authors.initials: LK
authors.lastname: Keefer
authors.forename: A N
authors.initials: AN
authors.lastname: Schechter
authors.forename: N
authors.initials: N
authors.lastname: Mohandas
mesh_terms: D000483:Alleles; D000755:Anemia, Sickle Cell / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D004909:Erythrocyte Indices / Q000235:genetics; D004912:Erythrocytes / Q000473:pathology; D005914:Globins / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism; D010108:Oxyhemoglobins / Q000032:analysis; D019076:Transgenes; D017086:beta-Thalassemia / Q000473:pathology
chemical_list: D006451:Hemoglobin, Sickle; D010108:Oxyhemoglobins; C029775:oxyhemoglobin S; D005914:Globins; D010100:Oxygen