ANGIOTENSIN II AND NEPHROGENESIS IN VITRO

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One-third of end stage renal disease in children results from abnormal renal growth (dysplasia). Although fetal renal development has been described morphologically, the molecular mechanisms underlying these changes are largely unknown. Angiotensin II (AII), a regulator of blood pressure and potent growth factor, is a prime candidate for a key role in the regulation of fetal nephrogenesis. Treatment of late gestation pregnant women with angiotensin converting enzyme inhibitors (ACE-I) has dire consequences for the developing fetus, including abnormal skull development and renal dysplasia. Affected infants require dialysis and transplantation for long-term survival. We hypothesize that growth factor effects of AII modulate fetal renal development, and that these actions occur even in the absence of altered fetal blood flow. Whether AII deficiency directly causes renal dysplasia or whether secondary growth factors are responsible has not been determined. The latter is likely, because AII upregulates several other growth factors known to be important in regulating renal development. In preliminary studies using cultured whole rat metanephroi, isolated from confounding maternal influences, we found that a) AII stimulated ureteric bud branching, b) ACE-I and type 1 AII receptor blockade caused decreased and aberrant branching and glomerulogenesis, while c) type 2 AII receptor antagonism increased branching and glomerulogenesis. We propose experiments to critically define the multiple roles of AII in nephrogenesis. Specific Aim 1. To test the hypothesis that fetal nephrogenesis is regulated by the growth factor effects of AII, with the type 1 (AT1) receptor playing a growth-promoting and the type 2 (AT2) receptor a growth-inhibiting or pro-apoptotic role. Specific Aim 2. To test the hypothesis that altered AII signaling leads to abnormal cell proliferation and apoptosis and to correlate these changes with altered morphogenesis. Specific Aim 3. To determine whether AII modulates nephrogenesis directly, or whether its effects are mediated by the potent growth regulators transforming growth factor beta (TGFbeta) and platelet derived growth factors (PDGF) both known to be induced by AII.