Cyclosporine impairs the guanylyl cyclase activity of the natriuretic peptide receptor in the glomerulus

Citation
H. Kook et al., Cyclosporine impairs the guanylyl cyclase activity of the natriuretic peptide receptor in the glomerulus, PHARMAC RES, 42(5), 2000, pp. 435-441
Citations number
31
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
PHARMACOLOGICAL RESEARCH
ISSN journal
1043-6618 → ACNP
Volume
42
Issue
5
Year of publication
2000
Pages
435 - 441
Database
ISI
SICI code
1043-6618(200011)42:5<435:CITGCA>2.0.ZU;2-A
Abstract
In order to elucidate the involvement of the atrial natriuretic peptide (AN P) and its receptor (natriuretic peptide receptor; NPR) system in cyclospor ine-induced nephrotoxicity, we investigated the cyclosporine A (CsA)-induce d changes in characteristics of the NPR/guanylyl cyclase system in the glom erulus and inner medulla of the rat kidney. CsA was administered intramuscu larly to rats for 2 weeks (CsA group). Particulate guanylyl cyclase activit y was measured in glomerular and inner medullary membranes. For receptor ch aracteristics, quantitative in \?itro receptor autoradiography was performe d. The guanylyl cyclase activity in the glomerulus from the CsA group was a ttenuated compared with that from the control. However, the activity in the inner medulla was not affected by CsA treatment. Direct application of CsA to normal glomerular membrane completely abolished the ANP-induced guanyly l cyclase activation. Binding studies, using I-125-ANP, revealed that B-max was decreased in the CsA group, while K-d was not affected in the glomerul us. However, in the inner medulla, neither B-max nor K-d was affected by Cs A treatment. CsA did not displace the I-125-ANP bindings to NPRs in the nor mal rat kidney. Local tissue ANP as well as plasma ANP concentration in bot h groups was not significantly different. These results indicate that CsA i mpairs the guanylyl cyclase activity mainly in the glomerulus by the decrea se in NPR population and/or by direct inhibition, suggesting that the ANP/N PR system might be involved in CsA-induced nephrotoxicity. (C) 2000 Academi c Press.