FULMINANT METANEPHRIC APOPTOSIS AND ABNORMAL KIDNEY DEVELOPMENT IN BCL-2-DEFICIENT MICE

Apoptosis of the developing metanephric kidney plays an important role in renal organogenesis. The bcl-2 is an oncogene that inhibits apopto tic cell death in a variety of settings. The bcl-2 (-/-) mice complete embryonic development but, in contrast to bcl-2 (+/-) and bcl-2 (+/+) littermates, manifest growth retardation, hypopigmentation of hair, l ymphoid apoptosis, abnormal kidney morphology, and renal failure postn atally. To provide insight into the mechanism for the latter abnormali ties, we examined metanephric kidneys from bcl-2 (-/-), bcl-2 (+/-), a nd bcl-2 (+/+) mice, as well as embryonic day 12 (E12) mouse embryos, and compared growth and development of metanephroi in vitro. Kidneys f rom bcl-2 (+/-) mice developed normally. In contrast, development of k idneys from bcl-2 (-/-) mice was abnormal as reflected by a marked red uction of renal size in newborns compared with kidneys of bcl-2 (+/-) littermates. In addition, kidneys from bcl-2 (-/-) mice contained far fewer nephrons and had smaller nephrogenic zones. Although metanephroi obtained from E12 bcl-2 (+/-) and bcl-2 (-/-) mouse embryos were comp arable in size, apoptosis of cells within metanephric blastemas of met anephroi from E12 bcl-2 (-/-) embryos was strikingly enhanced compared with that in blastemas of metanephroi from bcl-2 (+/-) embryos. Durin g 3 days in culture, growth and development of metanephroi from bcl-2 (-/-) embryos were visibly reduced compared with those from bcl-2 (-/- ) embryos. We conclude that the kidney abnormality in bcl-2-deficient mice is cell autonomous and that bcl-2 is required for normal metaneph rogenesis. In its absence, kidney size and nephron numbers are markedl y reduced. These abnormalities appear to result from excessive apoptos is within developing metanephric blastema.