Changes in glomerular thromboxane A2 receptor expression and ligand binding following immune injury. Kidney Int 1999 Jan;55(1):139-47
Date
01/20/1999Pubmed ID
9893122DOI
10.1046/j.1523-1755.1999.00227.xScopus ID
2-s2.0-0032898248 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
BACKGROUND: Thromboxane (Tx) A2 is a potent vasoconstrictor eicosanoid that attains high levels within nephritic glomeruli and mediates a drop in glomerular filtration rate (GFR). In the course of nephritis, however, GFR recovers despite high intraglomerular TxA2 levels. We hypothesized that this recovery indicates a reduced responsiveness of the glomerular vasculature to TxA2, and explored whether changes in TxA2 receptor protein expression and receptor-ligand binding are underlying mechanisms.
METHODS: Glomerulonephritis was induced in male Sprague-Dawley rats using an antibody raised in rabbits against rat particulate glomerular basement membrane (GBM). Changes in Tx receptor levels were assessed in protein lysates of glomeruli on days 3 and 7 after a single intravenous injection of the anti-GBM antibody. Ligand-binding studies were performed at the same time points using isolated glomeruli and the TxA2 receptor ligand [3H]-SQ-29,548. GFR was measured as the clearance of endogenous creatinine.
RESULTS: There was a marked increase in Tx receptor protein in the lysates of nephritic glomeruli on days 3 and 7. In contrast, binding sites (Bmax) of [3H]-SQ-29,548 decreased, indicating that the excess receptor became either inaccessible to its ligand (sequestered) or desensitized. Daily administration of the Tx synthase inhibitor Furegrelate starting prior to injection of anti-GBM antibody prevented the decrease in [3H]-SQ-29,548 binding. Furegrelate treatment starting in an established stage of nephritis had no effect. In these animals, GFR was lower than nephritic controls not treated with Furegrelate.
CONCLUSIONS: These observations indicate that in the course of glomerulonephritis, there is a marked increase in glomerular Tx receptor expression. The enhanced intraglomerular TxA2 synthesis causes either a sequestration or desensitization of its receptor. As a result, access of unbound TxA2 to efferent arterioles may become facilitated, and constriction of these arterioles may preserve GFR.
Author List
Bresnahan BA, Dufek S, Wu S, Lianos EAAuthor
Barbara A. Bresnahan MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBenzofurans
Disease Models, Animal
Enzyme Inhibitors
Glomerular Filtration Rate
Glomerulonephritis
Kidney Glomerulus
Kinetics
Ligands
Male
Rabbits
Rats
Rats, Sprague-Dawley
Receptors, Thromboxane
Thromboxane A2
Thromboxane-A Synthase
