Autosomal dominant polycystic kidney disease (ADPKD) affects about 400,000 U.S. citizens and is the 3rd or 4th leading cause of kidney failure accounting for 8-10% of all diaysis patients. Acquired cystic disease (ACD) develops in over one-half of patients maintained on dialysis for 3 years or longer. In these and the rarer autosomal recessive PKD (ARPKD) cysts develop from renal tubules that may enlarge to many centimeters in diameter. Cyst enlargement is associated with the increased rate of growth of renal tubule epithelial cells. It is hypothesized that cysts develop and enlarge secondary to abnormal proliferation of tubule epithelial cells, and that reduction of epithelial proliferation will slow or stop cyst growth.
The specific aims of this research are 1) to determine whether cell proliferation or fluid accumulation is the primary determinant of cyst enlargement; 2) to find candidate pharmacologic agents or extracellular conditions that will diminish epithelial cell proliferation in cysts and thereby slow cyst growth; 3) to determine the effects of the candidate pharmacologic agents and extracellular conditions on renal cyst dvelopment and growth, and on renal function in animals with hereditary and acquired renal cystic disroders; 4) to culture human cyst epithelial cells in vitro in order to determine the effect of candidate drugs and extracellular conditions on cell hyperplasia. Studies will be conducted in Madin-Darby canine kidney (MDCK) cells cultured within collagen or agarose gels to form cysts that progressively enlarge and fill with fluid as the cells proliferate. The rate of cell growth, cyst growth, transepithelial hydrostatic pressure, fluid pH,(Na), (K) and (Cl) will be determined following addition of candidate inhibitors of hyperplasia (e.g. amiloride, colchicine, hydroxyurea, increased (K) and decreased (Na). Cysts dissected from the Jackson C57 BL/6J cpk/cpk mouse and the Werder mouse (spontaneous diseases) and chemically acquired cystic diseases (diphenylthiazole, rat; methylprenisolone, neonatal rabbit) will also be studied in culture in the same format as MDCK cysts. Pharmacologic agents will be administered to mice, rats and rabbits with hereditary and acquired cystic disorders to determine the effect on cyst growth rate and renal function. Cell cycle analysis by flow cytometry will be performed on cells removed from cysts, and on cyst cells in culture. Successful completion of this research will justify the trial use of specific pharmacologic and dietary regimens in the treatment of human renal cystic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038980-05
Application #
3238614
Study Section
General Medicine B Study Section (GMB)
Project Start
1987-07-01
Project End
1993-06-30
Budget Start
1991-07-01
Budget End
1993-06-30
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Grantham, J J (1997) Mechanisms of progression in autosomal dominant polycystic kidney disease. Kidney Int Suppl 63:S93-7
Grantham, J J (1993) Polycystic kidney disease: hereditary and acquired. Adv Intern Med 38:409-20
Ye, M; Grant, M; Sharma, M et al. (1992) Cyst fluid from human autosomal dominant polycystic kidneys promotes cyst formation and expansion by renal epithelial cells in vitro. J Am Soc Nephrol 3:984-94
Neufeld, T K; Douglass, D; Grant, M et al. (1992) In vitro formation and expansion of cysts derived from human renal cortex epithelial cells. Kidney Int 41:1222-36
Harding, M A; Gattone 2nd, V H; Grantham, J J et al. (1992) Localization of overexpressed c-myc mRNA in polycystic kidneys of the cpk mouse. Kidney Int 41:317-25
Rankin, C A; Grantham, J J; Calvet, J P (1992) C-fos expression is hypersensitive to serum-stimulation in cultured cystic kidney cells from the C57BL/6J-cpk mouse. J Cell Physiol 152:578-86
Grantham, J J (1992) Regulation of cell proliferation and fluid secretion in the progressive enlargement of renal cysts. Contrib Nephrol 97:15-22
Gattone 2nd, V H; Grantham, J J (1991) Understanding human cystic disease through experimental models. Semin Nephrol 11:617-31
Grant, M E; Neufeld, T K; Cragoe Jr, E J et al. (1991) Arginine vasopressin stimulates net fluid secretion in a polarized subculture of cyst-forming MDCK cells. J Am Soc Nephrol 2:219-27
Takahashi, H; Calvet, J P; Dittemore-Hoover, D et al. (1991) A hereditary model of slowly progressive polycystic kidney disease in the mouse. J Am Soc Nephrol 1:980-9

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