The projects aim is to study the biological role of the endothelin (Et) system which includes the Et peptide and its receptors. Specifically, the project will examine the hypothesis that each of the Et receptor subtypes, EtA and EtB, is uniquely modulated by the Et ligand and this modulation is distinct from the usual ligand-receptor interactions. Thus, Et has little effect on the EtA subtype. By contrast, Et upregulates the EtB subtype. Each receptor subtype, in turn, modulates production of the Et peptide itself, such that EtA exerts a negative feedback to decrease Et production while a positive feedback to increase Et production occurs through the EtB receptor subtype. The EtB receptor subtype may also suppress Et production through nitric oxide (NO) and prostacyclin (PGI2). The functional consequence of Et activation will then be determined by the contribution of the distinct function of each receptor system whereby EtA mediates vasoconstriction and EtB mediates vasoconstriction or vasodilation. The projects will also examine a physiologic modulator of this system, the adrenergic nervous system, as well as a pathophysiologic modulator, cyclosporine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042159-06
Application #
2444035
Study Section
Pathology A Study Section (PTHA)
Project Start
1990-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hunley, T E; Kon, V (2001) Update on endothelins - biology and clinical implications. Pediatr Nephrol 16:752-62
Hunley, T E; Tamura, M; Stoneking, B J et al. (2000) The angiotensin type II receptor tonically inhibits angiotensin- converting enzyme in AT2 null mutant mice. Kidney Int 57:570-7
Hohenfellner, K; Hunley, T E; Yerkes, E et al. (1999) Angiotensin II, type 2 receptor in the development of vesico-ureteric reflux. BJU Int 83:318-22
Hohenfellner, K; Hunley, T E; Schloemer, C et al. (1999) Angiotensin type 2 receptor is important in the normal development of the ureter. Pediatr Nephrol 13:187-91
Gainer, J V; Hunley, T E; Kon, V et al. (1997) Angiotensin II type I receptor polymorphism in African Americans lower frequency of the C1166 variant. Biochem Mol Biol Int 43:227-31
Hunley, T E; Julian, B A; Phillips 3rd, J A et al. (1996) Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. Kidney Int 49:571-7
Fogo, A; Kon, V (1996) Treatment of hypertension. Semin Nephrol 16:555-66
Kon, V; Hunley, T E; Fogo, A (1995) Combined antagonism of endothelin A/B receptors links endothelin to vasoconstriction whereas angiotensin II effects fibrosis. Studies in chronic cyclosporine nephrotoxicity in rats. Transplantation 60:89-95
Hunley, T E; Iwasaki, S; Homma, T et al. (1995) Nitric oxide and endothelin in pathophysiological settings. Pediatr Nephrol 9:235-44
Hunley, T E; Fogo, A; Iwasaki, S et al. (1995) Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity. J Am Soc Nephrol 5:1718-23

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