Pathophysiology of a Sickle Cell Trait Mouse Model: Human αβS Transgenes with One Mouse β-Globin Allele,

As a potential model for sickle cell trait (AS), we examined mice containing one normal mouse β-globin allele in combination with a human hemoglobin S (hαβS) transgene (mβ/hS). The mice segregated into two subpopulations containing low and high proportions of hemoglobin S (mβ/hS1 and mβ/hS2, respectively) that was associated with one or two human hαβS transgenes. We noted striking kidney pathology (cortical cysts, hyperplastic tubules, and glomerulonephritis), increasing with age and with greater severity in mβ/hS1. mβ/hS2 animals were largely tolerant to 5% O2 for 1 h, whereas 80% of mβ/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 α/mouse β) hemoglobins with a mild β-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 P50, red cell indices, and genetic background are necessary in establishing potential relevance of any mouse model of the sickle cell syndromes.