RESUMO
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.
