Badr K F, DeBoer D K, Schwartzberg M, Serhan C N
Division of Nephrology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Proc Natl Acad Sci U S A. 1989 May;86(9):3438-42. doi: 10.1073/pnas.86.9.3438.
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.
脂氧素A4（LXA4）与[3H]白三烯D4（LTD4）竞争性地特异性结合培养的大鼠肾小球系膜细胞。LXA4在浓度为100 nM时可产生半数抑制作用，而未标记的LTD4产生半数抑制作用的浓度为10 nM。10 nM和50 nM的LXA4可使系膜细胞肌醇三磷酸生成量出现低水平但显著的增加：与溶剂对照组相比，分别增加48%和44%（而等摩尔的LTD4可使生成量分别增加146%和106%），在存在100倍浓度的LTD4受体拮抗剂SKF 104353时，这种增加被消除。此外，暴露于100 nM LXA4可抑制10 nM LTD4诱导的系膜细胞肌醇三磷酸生成。为了检验这些结果在体内的相关性，我们建立了肾内动脉注射LTD4对麻醉大鼠肾小球滤过率和肾血浆流量降低作用的剂量反应曲线（LTD4剂量为0.5、7.0、14.0和20.0微克/千克每分钟），同时或不同时给予1微克/千克每分钟的LXA4。在上述LTD4剂量下，给药期间肾小球滤过率/肾血浆流量的平均降低百分比分别为27%/24%、25%/40%、70%/65%和73%/70%（*与基线相比，P<0.05）。给予LXA4时，这些值如下：9%/20%、11%/37%、42%/51%和50%/68%，最后一个值代表LTD4/肾小球滤过率剂量反应曲线的偏移。因此，LXA4竞争[3H]LTD4与系膜细胞的结合，其存在可抑制LTD4诱导的肌醇三磷酸生成，且其自身对系膜细胞肌醇三磷酸的刺激可被LTD4受体拮抗剂阻断。在体内，LXA4可拮抗LTD4诱导的肾小球滤过率下降，但不拮抗肾血浆流量下降，这意味着可防止LTD4介导的肾小球超滤系数降低，这是系膜细胞收缩的结果。这些结果表明，LTD4和LXA4在大鼠系膜细胞的一个共同位点相互作用，在该位点LXA4引发部分激动剂反应，并竞争性拮抗LTD4的细胞和生理作用。此外，这些结果为白三烯和脂氧素之间可能在肾小球炎症期间起作用的潜在负反馈调节相互作用提供了证据。
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