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Journal of the American Society of Nephrology, Vol 5, 1630-1633, Copyright © 1995 by American Society of Nephrology

REGULAR ARTICLES

Guanosine triphosphate cyclohydrolase I regulates nitric oxide synthesis in renal proximal tubules

B Amoah-Apraku, SS Tang, JR Ingelfinger and NJ Guzman
Department of Pharmacology, University of Florida College of Medicine, Gainesville, USA.

The synthesis of nitric oxide by proximal tubule-inducible nitric oxide synthase requires tetrahydrobiopterin as a cofactor. To determine whether tetrahydrobiopterin synthesis is required for nitric oxide production, nitrite release by mouse proximal tubule cells treated with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of the rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin from guanosine triphosphate, guanosine triphosphate cyclohydrolase I, was measured. Treatment with lipopolysaccharide (0.1 micrograms/mL) and interferon- gamma (100 U/mL) for 12 h increased nitrite production from 2.7 +/- 0.2 to 25.4 +/- 1.3 nmol/mg of protein (P < 0.001; N = 9). 2,4-Diamino-6- hydroxypyrimidine (6 mM) reduced lipopolysaccharide/interferon-gamma- induced nitrite production by 53.1 +/- 3.4%. Sepiapterin, a substrate for tetrahydrobiopterin synthesis via the dihydrofolate reductase- dependent pterin salvage pathway, prevented the inhibition by 2,4- diamino-6-hydroxypyrimidine, an effect that was blocked by methotrexate. In conclusion, guanosine triphosphate cyclohydrolase I activity is required for cytokine-induced nitric oxide production by proximal tubular epithelium. The inhibition of guanosine triphosphate cyclohydrolase I could prove useful in the treatment of nitric oxide- mediated renal disorders.


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