Lipoxin A4 antagonizes cellular and in vivo actions of leukotriene D4 in rat glomerular mesangial cells: evidence for competition at a common receptor.
Lipoxin A4 (LXA4) was competitive with [3H]leukotriene D4 (LTD4) for specific binding to cultured rat glomerular mesangial cells. Half-maximal inhibition was obtained with 100 nM LXA4, compared with 10 nM for unlabeled LTD4. At 10 and 50 nM LXA4 induced low, but significant, increases in mesangial-cell inositol trisphosphate generation: 48% and 44% increases as compared to vehicle controls, respectively (compared with 146% and 106% increments obtained for equimolar LTD4), which were abolished in the presence of 100-fold concentrations of the LTD4 receptor antagonist, SKF 104353. In addition, exposure to 100 nM LXA4 prevented mesangial cell inositol trisphosphate generation induced by 10 nM LTD4. To test the in vivo relevance of these results, we established a dose-response curve for the reducing effects of intrarenal arterial LTD4 on glomerular filtration rate and renal plasma flow in anesthetized rats (LTD4 doses were 0.5, 7.0, 14.0, and 20.0 micrograms/kg per min) without or with LXA4 at 1 microgram/kg per min. Mean percent decreases in glomerular filtration rate/renal plasma flow during LTD4 administration were 27*/24, 25*/40*, 70*/65*, and 73*/70* at the above doses, respectively (*P less than 0.05 versus baseline). With LXA4, these values were as follows: 9/20*, 11/37*, 42*/51*, and 50*/68*, the latter value representing a shift in the LTD4/glomerular filtration rate dose-response curve. Thus, LXA4 competes for [3H]LTD4 binding to mesangial cells, its presence prevents LTD4-induced inositol trisphosphate generation, and its own stimulation of mesangial-cell inositol trisphosphate is blocked by an LTD4 receptor antagonist. In vivo, LXA4 antagonizes LTD4-induced falls in glomerular filtration rate but not renal plasma flow, implying prevention of LTD4-mediated reductions in the glomerular ultrafiltration coefficient, a consequence of mesangial-cell contraction. These results suggest that LTD4 and LXA4 interact at a common site on rat mesangial cells at which LXA4 provokes partial agonist responses and competitively antagonizes both the cellular and physiological actions of LTD4. Moreover, these results provide evidence for a potential counterregulatory interaction between leukotrienes and lipoxins that may be relevant during glomerular inflammation.
Badr
K F
KF
Division of Nephrology, Vanderbilt University School of Medicine, Nashville, TN 37232.
DeBoer
D K
DK
Schwartzberg
M
M
Serhan
C N
CN
D000818:Animals; D001667:Binding, Competitive; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005920:Glomerular Mesangium / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D044045:Lipoxins; D051381:Rats; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism*; D018077:Receptors, Leukotriene; D012079:Renal Circulation / Q000187:drug effects; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D003998:Dicarboxylic Acids; D006893:Hydroxyeicosatetraenoic Acids; D007295:Inositol Phosphates; D044045:Lipoxins; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C040527:lipoxin A4; D015544:Inositol 1,4,5-Trisphosphate; C052393:pobilukast