Biomaterial Database

Aggravation of polycystic kidney disease in Han:SPRD rats by buthionine sulfoximine. 1997

V E Torres, and R J Bengal, and R D Litwiller, and D M Wilson

Division of Nephrology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.

The administration of ammonium chloride or of sodium or potassium bicarbonate has marked effects on the development of polycystic kidney disease (PKD) in Han:SPRD rats. Because of the possibility that these effects are mediated by changes in redox metabolism, the aim of this study was to determine whether depletion of glutathione, the most abundant and important cellular thiol and scavenger of reactive oxygen species, would affect the development of PKD in this animal model. +/+ and cy/+ Han:SPRD rats were treated with: (1) L-buthionine(S,R)-sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for the synthesis of glutathione; (2) glutathione monoethyl ester (GME), a compound that is known to increase the intracellular levels of glutathione; or (3) BSO and GME. Treatment with these drugs was started at 3 wk of age, and the animals were killed at 6 or 8 wk of age. Renal levels of oxidized glutathione were significantly higher in cy/+ than in +/+ rats, whereas no significant differences in reduced glutathione were detected. The administration of BSO caused a marked reduction in the levels of glutathione. The administration of GME caused a significant increase in the levels of glutathione at 2 h, but not at 12 h, after the administration. The increase in the renal levels of glutathione 2 h after the administration of GME was less in the rats treated with BSO than in the rats not receiving this drug, indicating that in part the increase in glutathione level was due to de novo synthesis. BSO-induced glutathione depletion was accompanied by a marked aggravation of the renal cystic disease, as reflected by kidney weights, histological scores, and plasma urea concentrations. However, the administration of GME did not lessen the cystic disease and did not reverse the effects of BSO. The transient effect of GME administration and the simultaneous increases in the levels of cysteine and oxidized glutathione, in addition to reduced glutathione, may explain the lack of protection by GME. These data support the notion that changes in redox metabolism may affect the development of PKD.

UI	MeSH Term	Description	Entries
D007668	Kidney	Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.	Kidneys
D008297	Male		Males
D010084	Oxidation-Reduction	A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471).	Redox,Oxidation Reduction
D011922	Rats, Mutant Strains	Rats bearing mutant genes which are phenotypically expressed in the animals.	Mutant Strains Rat,Mutant Strains Rats,Rat, Mutant Strains,Strains Rat, Mutant,Strains Rats, Mutant
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005260	Female		Females
D005721	Glutamate-Cysteine Ligase	One of the enzymes active in the gamma-glutamyl cycle. It catalyzes the synthesis of gamma-glutamylcysteine from glutamate and cysteine in the presence of ATP with the formation of ADP and orthophosphate. EC 6.3.2.2.	gamma-Glutamyl-Cysteine Synthetase,Glutamylcysteine Synthetase,Glutamate Cysteine Ligase,Ligase, Glutamate-Cysteine,Synthetase, Glutamylcysteine,Synthetase, gamma-Glutamyl-Cysteine,gamma Glutamyl Cysteine Synthetase
D005978	Glutathione	A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides.	Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia