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The Effects of Epidermal Growth Factor in Polycystic Kidney Disease

The Effects of Epidermal Growth Factor in Polycystic Kidney Disease. Michael Kelsey. What is Polycystic Kidney Disease?. Polycystic Most common life threatening genetic disease Comes in two forms. Autosomal Recessive vs. Autosomal Dominant. Autosomal Allele Dominant Recessive.

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The Effects of Epidermal Growth Factor in Polycystic Kidney Disease

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  1. The Effects of Epidermal Growth Factor in Polycystic Kidney Disease Michael Kelsey

  2. What is Polycystic Kidney Disease? • Polycystic • Most common life threatening genetic disease • Comes in two forms

  3. Autosomal Recessive vs. Autosomal Dominant • Autosomal • Allele • Dominant • Recessive

  4. Formation of Cysts • Internal extension of renal collecting tubules • Expanding tubules form cysts • Cysts contain epidermal growth factor

  5. Epidermal Growth Factor Receptor • Binds with epidermal growth factor • Activates Tyrosine Kinase activity • Tyrosine Kinase causes cells to grow and multiply • Strong Correlation

  6. Is the increased activity of EGFR a direct path of renal cyst formation? • Genetic approach • Mice are engineered to have PKD • Both the orpk and wa2 mutations

  7. Homozygous orpk mutants vs wild type • Blots for the activity of tyrosine kinase phosphorylation of EGF • Increased in orpk mutants • Causes cystic lesions to develop in kidneys

  8. Histological Analysis • The Orpk mutant illustrates an abundance of cysts compared to the dual mutant orpk;wa2

  9. Cystic Severity • Phosphotyrosine levels associated with EGFR used to determine severity of cysts • A significant reduction of severity in orpk;wa-2 mutants

  10. A decrease in severity of cysts causes an increase in kidney function • Used a Western Blot to measure osmolality • An increase in levels of proteins within urine of orpk;wa2 mutants • Double mutants display a significant improvement of kidney function

  11. Conclusions • By introducing a dual mutant, orpk;wa2, the levels of EGFR specific tyrosine kinase activity were found to play a principle role in cyst formation • A reduction in Epidermal Growth Factor Receptor tyrosine kinase activity results in a decrease of cyst severity and an improvement in the tubular function of the kidney • A possible treatment could be derived by managing the over expression of EGFR in the collecting tubule of the kidneys or by blocking tyrosine kinase activity

  12. References • Fall, P.J., and L..M. Prisant. 2005. Polycystic Kidney Disease. J Clin Hypertens.10:617-25. • Igarashi P. and S. Somlo. 2002. Genetics and Pathogenesis of Polycystic Kidney Disease. J AM Soc Nephrol. 13: 2384-2398 • Murcia, N.S. W.E. Sweeny, and E.D. Avner. 1999. New insights into the molecular pathophysiology of polycystic kidney disease. Kidney International. 55: 1046-1187. • Richards, W.G., W.E. Sweeny, B.K. Yoder, J.E. Wilkinson, R.P. Woychik and E.D. Avner. 1998. Epidermal Growth Factor Receptor Activity Mediates Renal Cyst Formation in Polycystic Kidney Disease. J. Clin. Invest. 101: 935-939. • Sullivan, L.P., Wallace D.P. and Grantham J.J. 1998. Epithelial Transport in Polycystic Kidney Disease. Physiological Review. 78: 1165-1191. • Wilson, P.D. 1991. Aberrant epithelial cell growth in autosomal dominant polycystic kidney disease. Am J Kidney Dis. 6:17 • Ye, M., M. Grant, M. Sharma, L. Elzinga, S. SwGrantham, and V.E. Torres. 1992. Cyst fluid from human autosomal dominant polycystic kidneys promotes cyst formation and expansion by renal epithelial cells in vitro. Am Soc Nephrol. 4:984-94.

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