Developmental stage-specific involvement of angiotensin in murine nephrogenesis

Angiotensinogen-deleted mice (Agt-KO) show phenotypes of hypotension and re nal atrophy. To investigate whether an alternative pathway other than angio tensin II (AII), i.e., processed angiotensin fragments, may play a biologic al role in nephrogenesis, we analyzed a congenic line of Agt-KO fetuses and neonates derived from two sources: one (Agt-KO/He) from mating with hetero zygous angiotensinogen-deleted mice and the other (Agt-KO/Ho) from mating h omozygous angiotensinogen-deleted mice. Although Agt-KO/He did not show a t ypical phenotype at birth, these mice showed papillary atrophy 2 weeks late r and thereafter, a marked increase in renal size, i.e., pelvic dilatation. In contrast, Agt-KO/Ho showed renal abnormalities at birth and subsequentl y died. TUNEL staining and electron microscopy revealed that accelerated pa pillary apoptosis was present at birth in Agt-KO/Ho and caused abnormal pap illary development; however, apoptosis was not detected in Agt-KO/He, sugge sting that different mechanisms for the abnormal renal development exist in Agt-KO/He and Agt-KO/Ho. Two-week administration of an angiotensin fragmen t (3-8), angiotensin IV (AIV), to Agt-KO/He markedly attenuated the renal a trophy, decreasing the incidence from 81% to 14% However, administration of AIV to fetal Agt-KO/Ho through the mother did not decrease the incidence. This is marked contrast to AII, which prevented renal atrophy in both fetal and neonatal periods. It is therefore suggested that AIV is involved in ne phrogenesis in a developmental stage-specific manner.