Lipoxin A4 antagonizes cellular and in vivo actions of leukotriene D4 in rat glomerular mesangial cells: evidence for competition at a common receptor.

Abstract

Lipoxin A4 (LXA4) was competitive with [3H]leukotriene D4 (LTD4) for speciflc 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 gig/kg per min) without or with LXA4 at 1 ,ug/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 < 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 [3HJLTD4 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.Lipoxygenase products of arachidonic acid display a diverse array of biological activities (1) and may participate in mediating the functional consequences of glomerular inflammatory injury (2). When administered selectively into the renal artery of anesthetized rats, leukotriene D4 [LTD4) exerts vasoconstrictor effects, and lipoxin A4 [LXA4; (5S,6R,15S)trihydroxy-7,9,13-trans-11-cis-icosatetraenoic acid] elicits vasodilator responses in renal arterioles, but both reduce the glomerular capillary ultrafiltration coefficient (Kf) (3, 4). The latter results from the concerted contractile action of smooth muscle-containing glomerular mesangial cells, which reduces the glomerular capillary area available for ultrafiltration and, hence, Kf (5, 6). We have recently characterized the bi...

Lipoxins stimulate prostacyclin generation by human endothelial cells

“…Recent results indicate that LX& can block the binding of leukotriene D4 to its receptor [18], and results have been presented showing that LX& can inhibit leukotriene CA-induced responses [ 16,171. Taken together, these findings suggest that lipoxin & may act at the receptors for cysteinyl-containing leukotrienes in certain tissues.…”

Lipoxin A4 Antagonizes the Mitogenic Effects of Leukotriene D4 in Human Renal Mesangial Cells

“…In contrast to this essentially proinflammatory scenario, LX inhibit neutrophil recruitment to inflammed renal glomeruli in models of acute glomerulonephritis and attenuate LTD 4 induced smooth muscle and mesangial cell contractility (7,8,17,18). Furthermore, LXA 4 augments LTD 4 -induced decreases in GFR (6).…”

“…Therefore, in the context of effects on neutrophil trafficking, LX act as endogenous 'braking signals' in the inflammatory process (2,4,5). LXA 4 and LTD 4 have previously been shown to exert counter-regulatory roles on renal mesangial cell function (6)(7)(8)(9)(10). Mesangial cells are modified smooth muscle cells playing a pivotal role in renal physiology by regulating circulation and glomerular structural integrity.…”

“…Controversy exists as whether these agents act at distinct receptors in target cells (6,9,10) or whether LXA 4 antagonises the cellular and in vivo actions of LTD 4 by competing for a common receptor (6). 3 suggesting partial agonism (6).…”

Formation of a novel 20‐hydroxylated metabolite of lipoxin A4 by human neutrophil microsomes

“…LXA, inhibits leukotriene B, (LTB,)-induced inflammation in the hamster cheek pouch [6] and prior exposure of neutrophils to the lipoxin blocks the chemotactic response to LTB, [7,8]. Both the cellular and in vivo actions of leukotriene D, in renal microcirculation are antagonized by LXA, [9]. These activities suggest that LXA, may be associated with human diseases.…”