Unique endothelin receptor binding in kidneys of ETB receptor deficient rats.
Gariepy and colleagues (Gariepy CE, Williams SC, Richardson JA, Hammer RE, and Yanagisawa M. J Clin Invest 102: 1092-1101, 1998.) developed rescued spotting-lethal rats that carry a naturally occurring deletion of the endothelin (ET) type B receptor gene resulting in a lack of functional renal ETB receptor expression. It has been shown that rats homozygous (sl/sl) for the deletion have elevated plasma ET-1 levels; thus, the purpose of this study was to determine whether this deletion would result in a downregulation of ETA receptors in renal tissue. ET-1 and ET-3 binding experiments were performed with cortex, outer medullary, and inner medullary membranes of heterozygous (sl/+) and sl/sl ETB receptor-deficient rats. 125I-labeled ET-1 binding in sl/sl cortex and outer medulla was significantly lower than cortex and outer medulla from sl/+ rats. In contrast to sl/+ rats, [125I]ET-3 binding was not detected in the cortex and outer medulla of sl/sl rats, indicating a lack of ETB receptor expression. The inner medulla of sl/+ rats also demonstrated an abundance of ETB receptors. Surprisingly, however, we also observed significant [125I]ET-3 binding in the sl/sl inner medulla. Furthermore, ET-3 binding in the inner medulla could be blocked with an ETA receptor antagonist in sl/sl rats but not in tissue from sl/+ rats. These studies indicate that rats deficient in ETB receptors have decreased renal cortical and outer medullary ETA receptor number, most likely in response to elevated plasma ET-1 levels. In addition, homozygous ETB-deficient rats express a novel inner medullary ET-3 binding site.
Taylor
Traci A
TA
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA.
Gariepy
Cheryl E
CE
Pollock
David M
DM
Pollock
Jennifer S
JS
D000818:Animals; D000077868:Atrasentan; D001667:Binding, Competitive; D015536:Down-Regulation; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D019334:Endothelin-3 / Q000378:metabolism; D017353:Gene Deletion; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D008297:Male; D011759:Pyrrolidines / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains / Q000235:genetics; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
C120508:A 192621; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D000077868:Atrasentan