The objective is to identify factors that stimulate growth and regeneration of kidney epithelial cells in order to formulate new treatments of acute renal failure (ARF). In previous experiments in a rat model of ARF we found that infused amino acids acted directly on regenerating kidney tissue to stimulate phosphatidylcholine and protein biosynthesis and ameliorate renal functional insufficiency. Knowledge that normal serum components can enhance renal repair after injury led to recent studies using monkey kidney epithelial cells (BSC-1 line) in culture that identified other growth-stimulating factors such as vasopressin. During the course of ongoing experiments we were surprised to find that a striking stimulation of DNA synthesis occurred when purine nucleosides or nucleotides (PNs) were added to the culture medium of BSC-1 cells. The magnitude of the mitogenic effect of AMP or ADP, for example, was 3-fold greater than the previously observed maximal effect with other growth-promoting agents. This observation suggests that the provision of exogenous PNs could speed regeneration of the injured kidney epithelium following ARF by stimulating the proliferation of non-injured or sublethally-injured cells.
Specific aims of the proposed research are to: (1) Identify mechanisms by which PNs stimulate DNA synthesis and growth of kidney epithelial cells in culture. We will test the hypothesis that PNs increase DNA synthesis by producing growth-stimulators, and/or blocking generation of growth-inhibitors by the cells. (2) Determine the capacity of PNs to stimulate DNA synthesis in primary cultures of kidney epithelial cells obtained from rats with ARF; and (3) Define the effect of infused PNs on DNA synthesis in regenerating renal tissue in vivo. Elucidation of growth-regulating mechanisms in kidney cells could be an important step towards developing new treatments of ARF by speeding the recovery process.
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