The objective of this project is to study gene expression during renal maturational and hypertrophic growth with particular emphasis on the interaction between renal growth and angiotensin II (AII). The first hypothesis to be tested is that AII plays a role in regulating the growth of the developing and mature kidney, and in fact may be a growth factor for the kidney. The growth models to be used in testing this hypothesis are metanephric organ culture and unilateral renal artery infusion of AII. Experiments have been designed to quantitate the effects of AII or AII blockade on nephrogenesis by maturational staging and nephron counting, and by the degree of expression of stage-specific antigens. The mechanism of action of AII will be examined by studying the interaction between AII and both growth factors and proteins which have previously been demonstrated to play an important role in renal development. The effects of in vivo infusion of AII on the growth responses of the mature kidney will be studied by examining the effects of AII on the expression of early growth response genes in whole kidney, glomeruli, and tubules. More distal growth-related events will be studied including the effects of AII on the expression of proto-oncogenes and growth factors (TGF-beta and PDGF), on DNA and protein synthesis, and on compensatory renal growth following unilateral nephrectomy. The interaction between hemodynamics, growth and AII will be examined to differentiate the vasoactive from the growth effects of AII. The second hypothesis to be tested is that novel genes are involved in the regulation of the renal hypertrophy which occurs in the remaining kidney following unilateral nephrectomy, a growth state that appears to involve a unique mechanism of cell entry into the growth cycle. Hypertrophy-regulated genes will be identified by subtraction cloning. In view of the integral role of kidney growth in renal disease, insight into the mechanisms of kidney growth should have both biological and potentially therapeutic relevance.
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