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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018413-11
Application #
3226020
Study Section
General Medicine B Study Section (GMB)
Project Start
1978-06-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
11
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Pawar, S; Kartha, S; Toback, F G (1995) Differential gene expression in migrating renal epithelial cells after wounding. J Cell Physiol 165:556-65
Wagener, O E; Lieske, J C; Toback, F G (1995) Molecular and cell biology of acute renal failure: new therapeutic strategies. New Horiz 3:634-49
Aithal, N H; Walsh-Reitz, M M; Kartha, S et al. (1994) Glyceraldehyde-3-phosphate dehydrogenase modifier protein is associated with microtubules in kidney epithelial cells. Am J Physiol 266:F612-9
Lieske, J C; Toback, F G (1993) Regulation of renal epithelial cell endocytosis of calcium oxalate monohydrate crystals. Am J Physiol 264:F800-7
Toback, F G; Kartha, S; Walsh-Reitz, M M (1993) Regeneration of kidney tubular epithelial cells. Clin Investig 71:861-6
Kartha, S; Atkin, B; Martin, T E et al. (1992) Cytokeratin reorganization induced by adenosine diphosphate in kidney epithelial cells. Exp Cell Res 200:219-26
Toback, F G (1992) Regeneration after acute tubular necrosis. Kidney Int 41:226-46
Kartha, S; Toback, F G (1992) Adenine nucleotides stimulate migration in wounded cultures of kidney epithelial cells. J Clin Invest 90:288-92
Lieske, J C; Walsh-Reitz, M M; Toback, F G (1992) Calcium oxalate monohydrate crystals are endocytosed by renal epithelial cells and induce proliferation. Am J Physiol 262:F622-30
Walsh-Reitz, M M; Toback, F G (1992) Phenol red inhibits growth of renal epithelial cells. Am J Physiol 262:F687-91

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