Transgenic mice have been developed that express exclusively human sickle cell beta hemoglobin and have major pathological features found in humans with sickle cell disease. These mice provide a unique opportunity to investigate the fundamental mechanisms of this disease and to design new strategies to correct the associated genetic defect(s). We found that in breeding males expressing only adult human alpha-globin and sickle beta-globin (homozygous SS mice) with females containing these transgenes plus one copy of the mouse beta-globin gene (hemizygous SS mice) greater than expected numbers of hemizygous offspring were produced than homozygous mice (carrying no mouse beta-globin gene). These hemizygous mice, expressing the human alpha and sickle beta(s) transgenes in combination with mouse beta+/-, were used for our preliminary studies of their renal pathology. No kidney lesions were found in the control (129/Sv) mice, whereas about 50% of the hemizygous SS mice showed mild-to-severe kidney lesions, including glomerulonephritis, cystic atypical hyperplastic tubules, and general nephropathy. Kidneys of some hemizygous mice were normal or showed minimal nephropathy, yet those of the susceptible phenotype developed a mild-to-more-severe form of renal lesions. The tubular epithelium of kidneys of hemizygous mice of the more affected phenotype exhibited increased expression of inducible nitric oxide synthase with an increased 3-nitrotyrosine in close proximity. There was also a stronger immunostaining for vascular cell adhesion molecule-1 in the interstitial capillary cells as well as the tubular epithelial cells of the renal cortex, compared with normal control mice. The occurrence of a high incidence of renal abnormalities in our hemizygous SS mice suggests that these mice may provide a suitable model to study the pathogenesis of nephropathy resulting from altered blood flow and/or insufficient oxygen delivery.