Eicosanoid biosynthesis and role in renal immune injury

ULotriem ani Essentirl Fatty ML

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Eicosanoid Biosynthesis and Role in Renal Immune Injury

E. A. Lianos Department of Medicine, Division of Nephrology Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA. School of Health Sciences of the University of Crete, Iraklion, Greece

INTRODUCTION Renal immune injury is a major cause of chronic renal failure in patients entering a maintenance treatment program such as dialysis or transplantation. It can be initiated by deposition of antibody which binds to antigens present in glomerular or tubular basement membranes (i.e. Goodpasture’s syndrome) and on glomerular epithelial and mesangial cells (i.e. idiopathic membranous and IgA nephropathy), or of antibody which is a component of immune complexes deposited within glomerular or interstitial tissues (i.e. post-infectious and lupus injury may also be nephropathies) . Immune mediated by activated immunocompetent cells (macrophages, T lymphocytes) which invade glomerular or interstitial structures and mediate cell injury directed by antigen recognition (i.e. renal and certain proliferative transplant rejection glomerulopathies). Renal immune injury is frequently associated with vasoactive events (i.e. decrements in GFR and renal blood flow), inflammatory events (i.e. glomerular or tubulointerstitial infiltration by leukocytes), procoagulant events (i.e. platelet activation, fibrin formation), growth (as in proliferative and crescentic glomerulopathies) and matrix formation leading to sclerosis. These events account for its clinicopathological expression which includes rapidly progressive or indolent forms of renal failure, loss of glomerular capillary permselectivity (proteinuria) and progressive sclerosis leading to end stage disease. In the past decade we have witnessed an enormous effort to utilize the powerful methodological tools of modern biochemistry, physiology and molecular biology to identify the bioactive molecules which mediate the aforementioned events in the course of renal immune injury. Most investigative activity has focused on the glomerulus because it is this part of the nephron where renal immune injury is frequently initiated and because it is an easy structure to isolate in pure preparations

for biological studies. Moreover, the various glomerular cell populations (epithelial, endothelial, mesangial and resident macrophages) can be cultured or isol&d for biological studies. Using these methodological tools, significant contributions in our understanding of the pathobiology of renal immune injury were made. It is now recognized that the renal glomerulus provides a unique environment for an injurious factor (i.e. an antibody) to stimulate the synthesis of bioactive molecules (mediators) either by targeted endogenous glomerular cells or by recruited blood born cells. The spectrum of mediators which can originate from endogenous glomerular cells is diverse (eicosanoids, cytokines, growth factors, etc.) and it is beyond the scope and limits of this article to review all bioactive mediators identified to date. Instead, this review will focus on the biosynthesis and role of the eicosanoids, which occupy a central role in the biology of inflammation and the biologic effects of which can be associated with the pathophysiology underlying the expression and course of renal immune injury.

Reasons to explore the role of eicosanoids in renal immune injury The impetus for investigating the synthesis and role of eicosanoids in renal immune injury was based on two main lines of evidence: 1) early studies demonstrated that pharmacologic or dietary manipulation of the biosynthesis of eicosanoids or administration of certain eicosanoids can ameliorate the clinic0 pathological expression of certain forms of clinical and experimental immune glomerulopathies (1, 2) and 2) when the characterization and quantification of eicosanoid production by renal tissue became feasible and reproducible, it was realized that the glomerulus and its various cell populations can synthesize specific eicosanoids the biologic effects of which can be associated with most of the pathophysiologic se-

2

F’rostaglandinsLmkotrienes and Essential Fatty Acids

quellae of renal immune injury. Such associations are shown in Table 1 and are reviewed below. Table 1 Associations between specific eicosanoids and the pathophysiology

of renal immune injury

Process

Eicosanoid

Reference

Renal vasoactive events

TxA,, PGE, , PGI,, IZHETE, LTD,, LXA, PGF,, lZHETE, 15-HETE TxA,, PGF, 5-, 12-HETE, LTB,

11,7,8,25,28,74

Proliferation/growth Infiltration (leukocytes, fibroblasts) Coagulation/fibrin Matrix synthesis Immunoregulation

Arachidonic acid, TxA,, PGG,, PGH, TxA, LTC, * PGE,, PGE,, TxA,, 5-LO products

17,24 13,16,21,22,23

12 14,15 30,31,32,33,34, 35,36

* Phan S H, McCarty B M, Loeffler K M, Kunkel S L. Binding of Ieukotriene C, to rat lung fibroblasts and stimulation of collagen synthesis in vivo. Biochemistry 27: 2846-2853,1988.

Early studies on patients with glomerulonephritis and nephrotic range proteinuria demonstrated that administration of non-steroidal anti-inflammatory drugs such as Phenylbutazone (1) and Indomethacin (2) decreased proteinuria. On the other hand it was shown that exogenous administration of prostaglandins of the E series or administration of diets enriched with eicosapentaenoic instead of eicosatetraenoic (arachidonic) acid, ameliorated the expression of glomerular immune injury and prolonged the survival of mice with spontaneous Lupus glomerulonephritis (3, 4). In parallel with these observations, several investigators, working independently, described the synthesis in the isolated glomerulus of measurable amounts of eicosanoids originating both from the arachidonate cyclooxygenase and the lipoxygenase pathways (5, 6). The major arachidonate cyclooxygenation products detected in isolated glomeruli are PGF2, and PGE2. Thromboxane Az and the stable metabolite of PGIz, 6-keto-PGF,,, are synthesized in lesser amounts. PGEz and PGIz are potent vasodialators of the renal vasculature (7, 8) and inhibit platelet aggregation (9) and chemotaxis (10). In contrast, thromboxane A2 is a potent vasoconstrictor (11) and platelet aggregant (12) has for polymorphonuclear activity chemotactic leukocytes (13) and can mediate extracellular matrix synthesis (14, 15). PGF*, has been shown to enhance chemotaxis (16) and to be mitogenic (17). Independent observations have also demonstrated that the isolated glomerulus can synthesize arachidonate lipoxygenation products (6, 18, 19, can be detected in 20). These eicosanoids measurable amounts only when glomerular tissue is

stimulated by phospholipase Az activators such as the ionophore A~ls7. Under these conditions, 12HETE is the most abundant product. 5-HETE and LTB4 are also synthesized in lesser amounts (20), whereas no LTC4 synthesis has been described in normal glomeruli toLdate. These eicosanoids regulate chemotaxis and other leukocyte functions. Of the mono-HETEs, 12-HETE is the least potent in mediating chemotaxis of leukocytes (21). It can induce neutrophile and eosinophile chemokinesis in the absence of a concentration gradient and it also increases the intraneutrophile level of cyclic GMP (21, 22, 23). Moreover, 1ZHETE can promote growth (24) and can exert vasoactive effects; specifically, it antagonizes TxAz-mediatedvasoconstriction in aortic rings (25). 5-HETE and LTB4 are the most potent chemotactic eicosanoids (21) and stimulate the influx of calcium into polymorphonuclear leukocytes (26). Both of these eicosanoids enhance the expression of C3b receptors on neutrophiles and eosinophiles as well as the expression of IgG-receptors (21). Recent observations have demonstrated the presence of arachidonate 15-lipoxygenase activity in rat glomerular mesangial cells and the generation of lipoxins (27). This is of potential importance in glomerular inflammatory injury, as certain lipoxins (i.e. LxA4) are vasodilatory and may counteract the renal vasoconstrictor effects of leukotrienes (28). Moreover, lipoxins (A4 and B4) inhibit LTB,-mediated chemotactic responses of neutrophiles (29). Glomerular eicosanoids of the arachidonate cyclooxygenase and lipoxygenase pathways may also exert immunoregulatory effects. Thus, PGE2 is a potent inhibitor of interferon y (30) and has suppressive effects on mitogenesis and function of T cells (31), B cells (32), natural killer cells (32) and neutrophiles (34). A PGE analog, Enisoprost inhibits the response of human T cells and monocytes to mitogens (35). Drugs which inhibit the arachidonate lipoxygenase pathways increase the proliferation of mitogenically stimulated B cells (36). In contrast, inhibition of 5-lipoxygenase (using SC45662) has been shown to inhibit T cell and mononuclear cell responses to mitogens and IL-2 production (35). Such effects could be of importance in the regulation of intrareactions immune occurring following renal involving of immune injury and initiation immunocompetent cells such as the resident glomerula macrophages or activated lymphocytes/monocytes of blood origin.

Eicosanoid synthesis in renal immune injury The glomerular synthesis or urinary excretion (renal synthesis) of eicosanoids of the arachidonate cyclooxygenase or lipoxygenase pathways was inves-

Eicosmoid Biosynthesis and Role

tigated in a number of experimental and clinical forms of immune injury. Most experimental models of glomerular immune injury utilized in order to assess eicosanoid synthesis employed antibodies against defined endogenous glomerular or im‘planted’ antigens. Models of spontaneous mune complex nephritis, such as the murine lupus nephritis and of renal allograft rejection were also studied. Administration of antibodies against particulate glomerular basement membrane (Masugi nephritis) or against the brush border antigen FxlA nephritis) or against the (Passive Heymann thymocyte antigen Thy.-1, which is also expressed in mesangial cells, results in infiltrative, noninfiltrative and mesangiolytic/mesangio proliferative forms of glomerulonephritis, respectively (37, 38, 39). These experimental forms of antibody-mediated glomerular immune injury, therefore, span the spectrum of most clinicopathological forms of human immune glomerulopathies. In these models of immune injury, enhanced glomerular synthesis of eicosanoids was demonstrated. Of the arachidonate cyclooxygenation metabolites, the synthesis of thromboxane A2 is the most abundant and is sustained over the early and late phases of the disease (40). Of the arachidonate lipoxygenation metabolites, the synthesis of 1ZHETE is the most abundant and is also sustained (41). Glomerular leukotriene B4 synthesis is also enhanced but short lived whereas that of LTC4 is undetectable (20). Increased glomerular synthesis of these eicosanoids (TxA2 and LTB4) was also reported in immune complex glomerulonephritis induced by repeated injections of cationized bovine gamma globulin to the rat (42, 43), in experimental rat IgA nephropathy (44) in rat renal allografts undergoing acute rejection (45) and in mice with spontaneous Lupus nephritis in which enhanced cortical TxA2 synthesis was demonstrated (46) and in which preliminary observations indicate an increase in cortical LTB4 and LTC, synthesis as well (47). In clinical forms of renal immune injury enhanced urinary excretion of thromboxane B2, associated with reduced excretion of the 6-keto-PGFr, metabolite of PGIz was demonstrated in patients with active Lupus glomerulonephritis (48), whereas decreased urinary excretion of PGEz were demonstrated in patients with poststreptococcal glomerulonephritis (49). Enhanced urinary excretion of TxBz was also demonstrated in patients undergoing renal allograft rejection (50). Figure 1 is a schematic presentation of the glomerular eicosanoid synthetic profiles determined at early and late stages of antiglomerular basement membrane antibody-mediated injury in the rat. Table 2 summarizes clinical and experimental forms of renal immune injury in which changes in the synthesis or excretion of specific eicosanoids has been described.

in Renal Immune Injury 3

43 ._

K ii8 ._ : m

T‘bl

.A

2

PGI IPHETE

E

s

0

LT

2

4

6

8

24

48

Dav 12

12

TIME (hours)

Fig. 1 Glomerular eicosanoid synthetic profiles over a 2 week period following a single intravenous administration of anti-glomerular basement membrane antibody to the rat. Enhanced glomerular synthesis of HETE and leukotrienes occurs as early as 0.5 h following antibody administration and is followed by enhanced synthesis of glomerular thromboxane and prostaglandins. At 48 h, the glomerular synthesis of leukotrienes becomes impaired whereas that of thromboxane A,, prostaglandins and 1ZHETE is sustained throughout the two week period. The horizontal line indicates eicosanoid synthesis in normal glomeruli. The timing and pattern of glomerular polymorphonuclear leukocyte (PMN) infiltration (stippled area) and the onset of proteinuria (dotted diagonal line) are also shown to demonstrate the temporal correlation of these events with eicosanoid synthesis. Table 2 Enhanced eicosanoid synthesis/excretion immune injury

Anti-GBM disease Exp. membranous GN Exp. mesangioproliferative GN Exp. immune Complex GN Exp. IgA nephropathy Lupus nephropathy Renal allograft rejection

in renal

Eicosanoid

Reference

TxA,, PGE,, PGF,,, 5, lZHETE, LTB, TxA,, PGE?, LTB,

20,40

TxA,, lZHETE, LTB,

545563

TxA2, LTB,

42,43,88

TxAz

44

TxAr, LTB,, LTC, TxA2, LTB,, LTC,

46,47,48 45,50,75

53,12,73

Origin of eicosanoids in renal immune i?jury The demonstration that all four glomerular cell types (endothelial, epithelial, mesangial and resident macrophages) can synthesize specific eicosanoids and that glomerular.antibody deposition can be associated with infiltration by leukocytes and platelets, raises the obvious question; which cells do ‘glomerular’ eicosanoids originate from? This question is more than one of simple curiosity, since identification of the cellular source of eicosanoids will provide important information as to the mechanism by which antibody binding to a defined glomerular antigen mediates a clearly biochemical event; namely stimulation of the arachidonate cyclooxygenation or lipoxygenation. Several possibilities exist: a) binding of antibody to a defined

4

Prostaglandins Leukotrienes

and Essential Fatty Acids

glomerular cell antigen may directly induce enzymatic deesterification of arachidonate from membrane phospholipids and its subsequent cyclooxygenation or lipoxygenation to specific eicosanoids. Such mechanism could operate in those forms of glomerular injury mediated by antibody binding to antigens such as the glomerular epithelial cell FxlA or the mesangial cell Thy-l. For example, the Thy-l. antigen is a glycoprotein bound to the cell membrane through a phosphoinositol-containing membrane-binding domain (51) and antibody binding to Thy-l could mediate the release of phosphoinositol bound arachidonate; b) antibody binding to defined glomerular antigens could initiate activation of the complement system, the products of which (i.e. C3a, C5a, C5b-9) could directly mediate arachidonate release and eicosanoid synthesis. Evidence for such a mechanism comes from observations demonstrating the ability of specific anaphylatoxins to induce HETE and LT synthesis in mixed cell populations (52); c) chemotactic or proaggregatory molecules generated following glomerular antibody deposition could mediate recruitment of leukocytes or intraglomerular aggregation of platelets and eicosanoid release from these non-glomerular sources. This possibility was explored in anti-glomerular basement membrane antibody-mediated nephritis in the rat in which glomerular infiltration by neutrophiles and platelets is prominent. It was demonstrated that glomerular IZHETE synthesis was enhanced and that in platelet depleted rats, the glomerular synthesis of 12-HETE was no different than in platelet replete controls receiving anti-GBM antibody (41). In the same disease model, glomerular 5-HETE and LTB4 synthesis were also found to be enhanced (20). Neutrophile depletion prior to administration of only partially reduced anti-GBM ‘antibody glomerular synthesis of these eicosanoids. Moreover, there was no temporal correlation between peak eicosanoid synthesis and peak glomerular neutrophile infiltration (20). In contrast, complement depletion prior to administration of anti-GBM antibody was associated with a marked reduction in glomerular arachidonate lipoxygenation products. Similar observations were made in non-infiltrative complement-dependent models of glomerular immune injury, such as the passive Heymann nephritis and the antithymocyte antibodyinduced nephritis in which complement depletion prior to administration of anti-FxlA or anti-Thy-l antibodies significantly reduced glomerular LTB4, 1%HETE and thromboxane Bz synthesis (53, 54). These observations indicate that in complement dependent models of immune injury, complement activation mediates the increase in glomerular eicosanoid synthesis and that recruited leukocytes and platelets do not entirely account for the increments in glomerular eicosanoid syrithesis.

The issue of origin of eicosanoids in glomerular immune injury becomes even more intriguing when one considers the following observations: a) cultured glomerular epithelial or mesangial cells do not synthesize arachidonate lipoxygenation products when incubated with phospholipase A2 activators (i.e. A231s7) known to induce HETE and LT synthesis in cells capable of arachidonic lipoxygenation. Yet, normal isolated glomeruli stimulated by the same activators do synthesize immunoassayable amounts of HETE and LTB4 (19, 20, 41); b) incubation of isolated glomeruli with antibodies against the epithelial cell antigen FxlA or the mesangial cell antigen Thy-l in the presence of a complement source (serum) does not result in enhanced LT synthesis (55); c) whole body xirradiation to induce bone marrow depletion also results in depletion of glomerular resident macroph,ages and a significant reduction in glomerular LTBJ synthesis by normal as well as by immunologically injured glomeruli (55). These observations suggest that the mere antibody binding to glomerular cell antigens cannot explain the enhanced glomerular synthesis of arachidonate lipoxygenation products which occurs when antibody is used to induce glomerular injury in vivo. The studies also suggest that the bone marrow derived glomerular resident macrophage could be an important source of these eicosanoids when glomerular immune injury is induced in vivo. Strong evidence implicating this cell as a source of glomeruIar eicosanoids is provided by studies using essential fatty acid deficient diets. When rats are fed essential fatty acid deficient diets for 8 weeks so that phospholipid stores are depleted of tissue arachidonic acid, a significant reduction in the number of glomerular resident macrophages occurs along with reduced glomerular synthesis of PGEz, TxAi and LTB4 (56,57). In summary, the origin of eicosanoids in the immunologically injured glomerulus requires further exploration. Glomerular epithelial and mesangial cells do not synthesize arachidonate lipoxygenation products and infiltration by blood borne eicosanoid producing cells following initiation of immune injury in vivo does not entirely account for the increments in glomerular synthesis of these eicosanoids observed in vitro. The glomerular resident macrophage is a likely source of eicosanoid (mainly HETE and LT) via incompletely understood mechanisms.

ROLE OF EICOSANOIDS INJURY

IN RENAL IMMUNE

The demonstration that enhanced glomcrular eicosanoid synthesis occurs following initiation of immune injury raises the following question: are

Eicosanoid Biosynthesis and Role in Renal Immune Injury

eicosanoids simply markers of renal cell injury or infiltration by eicosanoid producing cells or do they also play a role in the pathobiology of immune glomeruiopathy? There are good reasons to raise this question. For example, in the model of passive Heymann nephritis, mediated by antibody against the glomerular epithelial cell antigen FxlA, enhanced glomerular synthesis of prochemotactic eicosanoids (i.e. LTBJ is observed (53). Yet, glomerular infiltration by leukocytes does not occur. Moreover, the vasoactive effect of eicosanoids (best studied for thromboxane AZ) on antibody mediated renal hemodynamic impairment (decrements in GFR) is transient, despite sustained increments of vasoconstrictor eicosanoids (TxA,) (58). There is increasing evidence that eicosanoids do indeed play a role in the pathophysiology of renal immune injury. This evidence is based on studies using pharmacologic manipulation of eicosanoid dietary manipulation of synthesis or action, eicosanoid synthesis and exogenous administration of specific eicosanoids. Effects of arachidonate cyclooxygenase inhibition Early studies using non-steroidal anti-inflammatory drugs (Phenylbutazone or Indomethacin) in doses which inhibit renal arachidonate cyclooxygenation to prostaglandins and thromboxanes demonstrated that these drugs decrease urinary protein excretion as well as glomerular filtration rate in patients with glomerulopathies chronic and the nephrotic syndrome (1, 2). In order to dissect the two effects subsequent studies assessed the immediate and longer term (5day) effects of Indomethacin on urinary protein excretion and on renal function in patients with the nephrotic syndrome primarily due to membranous nephropathy and focal glomerulosclerosis and with glomerular filtration rates ranging from near normal to moderately impaired (59). When Indomethacin (a single dose of 75 mg P.O. followed by a daily dose of 50 mg) was given in volume depleted patients, protein excretion was reduced by 45%. This decrement in proteinuria was more than two times greater than the fall in creatinine clearance and it was observed both acutely (1 h following the 75 mg P.O. dose) and over a five day period. This effect was blunted when Indomethacin was given in volume expanded patients. It was concluded that, since urinary protein excretion was reduced to a greater extent than GFR, mechanisms other than the hemodynamic effect of Indomethacin may mediate the decrements in urinary protein excretion. The effect of arachidonate cyclooxygenase inhibition on renal function was also assessed in patients with active lupus nephritis. It was found that the urinary excretion of immunoreactive prostaglandin E was significantly higher compared to that found

5

in normal subjects. Aspirin administration (4.8 g/day) decreased urinary immunoreactive PGE excretion as well as GFR and effective renal blood flow (60). These changes were reversible. In another clinical study the effect of cyclooxygenase inhibition was assessed in 20 hospitalized women with chronic immune glomerular disease in 18 of which the diagnosis was confirmed by renal biopsy. Two patients had the nephrotic syndrome and five patients fulfilled the criteria for the diagnosis of systemic lupus erythematosus. It was found that the urinary excretion of the 6-keto-PGFt, metabolite of prostacyclin was significantly reduced whereas excretion of urinary prostaglandin E2 was unchanged (61). One week treatment with Ibuprofen (1.2 g/day) markedly reduced the urinary excretion of both eicosanoids and this was associated with decrements of the glomerular filtration rate (GFR) and renal blood flow (RBF) by 28% and 35% respectively. These changes were inversely related to the urinary excretion of 6-keto-PGF,, but not to that of PGEr. No changes were observed in healthy women in response to Ibuprofen administration despite similar suppression of renal prostacyclin synthesis. In contrast to Indomethacin, administration of Sulindac for 1 week (0.4 g/day) did not affect renal prostacyclin synthesis or renal function despite a marked inhibition of extra renal cyclooxygenase activity. It was concluded that Sulindac may be a safe substitute for other non-steroidal antiinflammatory drugs in patients with chronic immune glomerulopathies (61). Whereas the aforementioned studies do not provide strong evidence for a role of arachidonate cyclooxygenation products in altering glomerular permeability to protein, they do point to a critical dependence of renal hemodynamics on these eicosanoids in immune glomerulopathies. This dependence makes the use of non-steroidal antiinflammatory drugs unwarranted in most immune glomerulopathies. A notable exception could be the use of low dose aspirin which selectively inhibits platelet-derived thromboxane as is reviewed below. Inhibition/antagonism of thromboxane The rationale for assessing the effect of thromboxane synthesis in glomerular immune injury is based on observations demonstrating enhanced glomerular synthesis or urinary excretion of this eicosanoid in clinical and experimental forms of renal immune injury (Table 2). Moreover, thromboxane receptors have been identified and characterized in glomeruli (62). The development of pharmacologic inhibitors of thromboxane synthesis and of antagonists of the thromboxane receptor resulted in important observations on the role of this eicosanoid in the pathophysiology of renal immune injury. Thromboxane synthase inhibition

6

Prostaglandins Leukotrienes and Essential Fatty Acids

using the pyridyl methyl phenyl-methylacrylate compound OKY1581 (ON0 Pharmaceutical) or the imidazole methyl-indolepropanoic acid compound UK38485 (Pfizer), ameliorates decrements in glomerular filtration rate at the early stages of antiglomerular basement membrane antibody-mediated glomerular injury (40). Thromboxane A2 receptor antagonism using the 7-oxabicyclo heptane compound ameliorates SQ-29,548 anti-Thy-l antibody-mediated acute decrements in GFR and RBF due to mesangial cell injury (63). In later stages of anti-GBM disease (day 14), glomerular filtration rate may not be reduced despite significant increments in glomerular thromboxane levels and the thromboxane synthase inhibitor UK 38485 has no effects (58). Moreover, enhanced glomerular thromboxane synthesis does not mediate decrements in glomerular filtration rate in rats with glomerular injury induced by deposition of immune complexes formed by consecutive injections of cationized bovine gamma globulin (42). In another model of glomerulonephritis induced by ferritinanti-ferritin immune complexes in Dahl-salt sensitive rats, chronic administration of the thromboxane synthase inhibitor OKY-046 (imidazolyl methylphenyl propenoic acid) was demonstrated to have a beneficial effect on renal function (clearance of creatinine), proteinuria and glomerular histology (64). In murine Lupus nephritis, also a model of mediated glomerulopathy, complex immune thromboxane receptor antagonism was shown to improve GFR in the early stages of the disease (65). The role of thromboxane in mediating impairment on renal function was also investigated in acutely rejecting renal allographs in rats. Kidneys transplanted from Lewis rats to Brown-Norway undergoing acute rejection recipients and demonstrated marked decrements in clearances of inulin and PAH. As renal function deteriorated, thromboxane B2 production by ex vivo perfused renal allographs increased progressively, whereas PGEz and 6-keto-PGF1, production remained unchanged (45). There was a significant inverse correlation between the in vivo clearance of inulin and the log of ex vivo thromboxane B2 production. Infusion of the thromboxane synthetase inhibitor UK-37248 (Imidazol ethoxy benzoic acid, Dazoxiben) into the renal artery of three day allografts significantly dereased urinary thromboxane B2 excretion and partially but significantly increased renal blood flow and glomerular filtration rate. Daily treatment with cyclophosphamide also improved GFR and RBF and reduced thromboxane production by renal allogafts (45). In the same disease model, the effect of chronic administration of the thromboxane synthase inhibitor, OKY-046, was evaluated. In animals receiving 75 mg/kg/day of OKY-046 by intermittent intraperitoneal injections,

allograft function was not improved and neither was thromboxane production inhibited. In contrast, animals receiving an equivalent dose of OKY-046 by continuous intra-arterial infusion for four days, maintained GFR and RBF at levels not different from those of non-rejecting isografts (66). In these animals OKY-046 significantly reduced renal allograft thromboxane Bz production as well as urinary thromboxane B2 excretion. Despite the beneficial effects on allograft function, OKY-046 did not alter the morphologic appearance of the cellular infiltrate nor the systemic proliferative and cytotoxic antidonor cellular immune responses. The effects of chronic administration of the thromboxane synthetase inhibitor OKY-046 were also evaluated on in situ and systemic alloimmune effector cell function in rejecting rat renal allografts. At four days following transplantation of fully allogeneic kidneys (ACI, RTla) into PVG (RTIC) rats, spleen cells and inflammatory cells eluted from the graft were assessed. It was found that the frequency of anti-donor precursor cytotoxic T cells was consistently lower in the allografts from OKY-046treated animals (continuous intraarterial infusion, 50 pg/kg/min) compared with those receiving vehicle treatment (67). In short term cultures (lo-15 days), lymphocytes from treated and control allografts were equally proficient in specifically lysing donor targets. Proliferative response to donor stimulators, measured by mixed lymphocyte reaction assays, were consistently greater in spleen cells than in allograft eluate cells, but there were no significant differences between OKY-046 and vehicle treated groups in terms of either splenocyte or allograft eluate proliferative responses (67). These studies on experimental models of renal allograft rejection implicate thromboxane as a hemodynamic mediator of renal impairment during the early stages of acute renal allograft rejection and also point to a role of this eicosanoid in regulating cytotoxic T cell function. In clinical studies involving patients with kidney allografts undergoing rejection, enhanced urinary immunoreactive excretion of TxB2 was demonstrated (50). Studies also assessed the correlation between thromboxane AZ formation and the cytologic inflammatory cell score of fine needle renal parenchymal aspirates. It was shown that the score correlated significantly with thromboxane B, formation originating from cells in the aspirate. A significant correlation was also shown to exist between the percentage of monocytes and macrophages in the aspirates and thromboxane B2 formation from these cells (68). These data support the contention that the enhanced urinary thromboxane B2 excretion in these patients is a useful marker of renal allograft rejection. Clinical studies afso assessed the role of throm-

EicosanoidSiosynthesisand Role in Renal Immune Injury boxane in mediating renal functional impairment in patients with active lupus nephropathy. In a randomized, double blind, crossover study, ten patients with biopsy proven lupus nephritis were given a 48-h continuous infusion of the selective thromboxane receptor antagonist BM13,177 (a sulfonamide phenyl carboxylic acid). These patients had markedly elevated baseline urinary thromboxane B2. Infusion of the TxAz receptor antagonist increased the inulin and PAH clearances significantly along with increments in urinary sodium excretion (69). The bleeding time doubled indicating occupancy of platelet thromboxane receptors. In a group of patients studied in parallel, low dose aspirin (20 mg twice daily for four weeks) produced a selective cumulative inhibition of platelet cyclooxygenase activity and a doubling of bleeding time. Yet, it had no effect on inulin clearance or on the urinary levels of thromboxane B2 or 6-keto-PGFr, excretion. The studies provide evidence that impairment of renal function in active lupus nephritis is at least partially mediated by enhanced thromboxane synthesis and that platelets are not a major source of thromboxane A2 synthesis and action within the kidney. In another study on patients with proliferative lupus nephritis, it was shown that active renal disease was accompanied by a decrease in the glomerular filtration rate without a decrease in the effective renal plasma flow resulting in marked depression in the filtration fraction. During recovery from active renal disease, the filtration fraction improved (70). As urinary excretion (renal synthesis) of vasodilatory prostaglandins were found to be increased in patients with active lupus nephritis and cyclooxygenase inhibition reduces GFR (60), it was hypothesized that the depression of filtration fraction may result from an increase in intrarenal production of vasodilatory prostaglandins during active disease. The observations accrued from these studies indicate that in patients with active lupus nephritis the effects of vasodilatory prostaglandins may oppose and outweigh the vasocontrictor effects of thromboxane A2 on renal blood flow and that the latter specifically contributes to the impairment of GFR. The effects of enhanced glomerular thromboxane synthesis on glomerular permeability to protein were also investigated in various models of glomerular immune injury. The results of these studies have been contradictory. In anti-GBM antibody mediated glomerular injury in rats, long term administration of a thromboxane synthase inhibitor OKY-1581 had no effects on urinary protein excretion (58). In a rat model of unilateral glomerulonephritis induced by in situ formation of cationic immune complexes, the thromboxane synthase inhibitor UK 38,485 did not ameliorate proteinuria or glomerular hypercellularity at 24 h

7

after induction of glomerular injury despite inhibition of both glomerular and systemic thromboxane synthesis (71). In contrast, in a variant model of passive Heymann nephritis, thromboxane synthase inhibition using OKY-046 significantly reduced proteinuria at the early stages of injury (2 hrs) and this effect was independent of changes in renal hemodynamics (72). At later stages of glomerular injury in passive Heymann nephritis, thromboxane synthase inhibition using the UK-3485 inhibitor had no effect (73). In summary, pharmacologic inhibition of thromboxane synthesis or antagonism of its receptor ameliorates the impairment in glomerular filtration rate and renal blood flow occurring at early or active stages of renal immune injury due to either antibody deposition (i.e. anti-GBM disease, lupus nephritis) or to immunocompetent cell activation (i.e. transplant rejection). At later stages of injury, inhibition of thromboxane synthesis does not have a significant effect on impaired renal hemodynamics despite sustained increments in the synthesis of thromboxane. _ Enhanced thromboxane synthesis may also have an immunoregulatory effect on immunocompetent cells involved in renal immune injury. Finally, most experimental evidence indicates that in antibody-mediated glomerular immune injury the enhanced glomerular thromboxane synthesis does not specifically mediate alterations in glomerular permselectivity to protein. Inhibition/antagonism of leukotrienes Although there have been no definitive reports demonstrating enhanced LTD4 synthesis in experimental glomerular immune injury, systemic administration of the LTD4 receptor antagonist SKF104353 was shown to prevent the acute decrements in glomerular ultrafiltration coefficient and single nephron GFR in anti-GBM antibody induced glomerular injury in the rat (74). Enhanced renal cortical synthesis of leukotriene B4 and C4 was demonstrated in acutely rejecting renal allografts in the rat (75) and in murine Lupus nephritis (47) and correlated inversely with decrements in GFR. The effect of pharmacologic manipulation of LT synthesis or action in these models awaits investigation. Dietary manipulation of eicosanoid synthesis The rationale for attempting to alter endogenous eicosanoid synthesis via manipulations of dietary fatty acid, was based on early observations made in native Greenland Eskimos in whom prolonged bleeding times, abnormal platelet function and low incidence of thrombosis and atherosclerosis were found to be related to the lipid composition of their marine diets and specifically to the replacement of

8 ProstaglandinsLeukotrienes and Essential Fatty Acids arachidonic acid in platelets by eicosapetaenoic acid which is an abundant constituent of lipids in marine animal tissues (76). It was reasoned, therefore, that in eicospentaenoic acid-enriched diets the endogenous synthesis of non dienoic eicosanoids would predominate and that these eicosanoids would lack the vasoactive, proaggregatory or proinflammatory effects mediated by dienoic (originating from arachidonic acid) eicosanoids. Moreover, eicosanoids originating from eicosapentaenoic acid, such as the trienoic leukotrienes, may have antithrombotic effects (77). This strategy was supported by early studies performed in NZB/NZW mice which develop a spontaneous systemic lupus erythamatosus-like syndrome, including proliferative glomerulonephritis. It was shown that treatment of these animals with exogenous prostaglandin El in large doses had a beneficial effect on survival and on the clinicopathologic expression of proliferative glomerulonephritis (3). Based on these observations the effects of diets containing a high concentration of linoleic acid and of diets deficient in linoleic acid and, therefore, deficient in this fatty acid precursor of dienoic eicosanoids were assessed in NZB/NZW FI mice. It was shown that all disease manifestations were strikingly ameliorated in the animals fed linoleic acid deficient diets (coconut oil containing less than 1% linoleic acid) compared to animals fed diets rich in linoleic acid (provided in the form of safflower oil, containing 78% linoleic acid) (78). The beneficial effects included a markedly prolonged survival, reduced severity of the clinic0 pathological expression of glomerulonephritis and lower levels of anti-nuclear antibody and anti-DNA antibodies in the animals fed essential fatty acid deficient diets. These observations were supplemented by studies performed in the same disease model and using dietary enrichment with the polyunsaturated fatty acid, eicosapentaenoic acid. It was demonstrated that, in contrast to-mice fed beef tallow (containing less than 0.05% eicosapentaenoic acid), mice fed menhaden oil enriched diets (containing 14.4% eicosapetanoic acid) did not develop proteinuria and had a prolonged survival (79). Similar observations were made in MRL-lpr mice with lupus nephritis (80) and in rats with accelerated nephrotoxic serum nephritis (81). In mice with spontaneous lupus nephritis fed diets rich in eicosapentaenoic acid, suppressive effects on the system (lesser degree of lymphoid immune hyperplasia, lower levels of circulating immune complexes) were also noted (80). The mechanism of the ameliorative effect of eicosapentaeinoic acid rich diets has not been elucidated. These diets appear to exert protective effects on the progression of the glomerulopathy despite a lack of suppression of anti-double stranded DNA antibody levels and their protective effect can be shown even when in-

itiated following the onset of nephropathy (82). A beneficial effect of eicosapetanoic acid rich diet on the rate of progression of renal failure (assessed by monitoring of the reciprocal creatinine) has also been reported in patients with IgA nephropathy (83). Of significant interest are the observations made in studies assessing the effects of essential fatty acid deficient diets on glomerular eicosanoid synthesis. It was demonstrated that essential fatty acid deficiency results in impaired glomerular synthesis of PGEZ and thromboxane B2 in response to stimuli such as angiotensin II and platelet activating factor (56) as well as impaired synthesis of glomerular leukotriene B4 in response to the ionophore A23187 (57). The impaired synthesis of these eicosanoids was specifically attributed to depletion of glomeruli of resident immunocompetent macrophages (57). These observations, therefore, implicate the glomerular macrophage as a major source of glomerular eicosanoids and particularly those originating from arachidonate lipoxygenation. The observations may also have significant therapeutic application. This was demonstrated in a model of renal allograft rejection in rats (84). Kidneys from rats fed essential fatty acid deficient diets and depleted of resident macrophages survived and functioned when transplanted across a major histocompatibility antigen barrier in the absence of immunosuppression of the recipient. Control allografts from rats fed essential fatty acid replete diets were rejected promptly. The renal allografts from donors subjected to essential fatty acid deficient diets were repopulated with host macrophages in five days. Administration of Ia-positive splenic leukocytes to the recipients of the essential fatty acid deficient kidney allogafts resulted in severe rejection of these allografts. Splenocytes originating from essential fatty acid deficient or control rats were equally effective in reducing rejection of the kidney allograft, indicating that the essential fatty acid deficient state did not protect the allograft against the effector phase of immune sensitization but it prevented the induction of immune sensitization. Preliminary observations also demonstrated a beneficial effect of essential fatty acid deficient diet in antiglomerular basement membrane antibodymediated decrements of single nephron glomerular filtration rate, plasma flow and the ultrafiltration coefficient as well as on proteinuria. These ameliorative effects were accompanied by significant suppression of glomerular eicosanoid (LTB4 and TxB2) synthesis (85). Effects of eicosanoid administration on renal immune injury Systemic administration of the stable prostaglandins PGEi was demonstrated to ameliorate glomerular

Eicosanoid Biosynthesis and Role in Renal Immune Injury

hypercellularity, antibody deposition and proteinuria and to prolong survival of NZB x NZW and of MRL(1 mice with murine lupus-associated nephritis (3, 86). Treatment of NZB/NZW F1 mice with PGE2 or Illoprost, a synthetic prostacyline analog, also had beneficial effects on proteinuria and survival (87). Beneficial effects of PGEz treatment have also been demonstrated in a murine model of apoferritin-induced immune complex and were associated with glomerulonephritis reduced production of anti-apoferritin antibody (88). Similar effects were also described in rats with anti-GBM disease treated with the stable compound (S)-15methyl-PG&. Glomerular hypercellularity and proteinuria were reduced (89). The ameliorative effects of these eicosanoids on the expression and course of renal immune injury have been attributed to their suppressive effect on mitogenesis or on function of immunocompetent cells, as reviewed above. CONCLUSIONS A proposed scheme of pathobiologic events occurring in renal immune injury is shown in Figure 2. RENAL IMMUNE INJURY (htibodyor cell-medmted)

Parsnchymal

cells

mediate pathophysiologic processes occurring in renal immune injury; namely, vasoactive effects leading to hemodynamic perturbations, growth (as in proliferative glomerulopathies) extracellular matrix synthesis and immunoregulation. On the other hand, eicosanoids either individually or in synergism may act in a paracrine or autocrine manner to sustain synthetic or proliferative activity of cells of their origin. Our knowledge on the cellular/molecular events leading to enhanced eicosanoid synthesis following initiation of antibody or cell-mediated renal immune injury is incomplete. There is increasing experimental and clinical evidence that inhibition of the synthesis or action of certain eicosanoids such as TxAz and leukotrienes using either pharmacologic or dietary means ameliorates the pathophysiologic and histopathologic expression of renal immune injury. Critical experimental and clinical research is needed to solidify the evidence that pharmacologic or dietary manipulations of eicosanoid synthesis have therapeutic implications in the management of renal immune injury.

Acknowledgement The author is supported by a United States Public Health Service (National Institutes of Health) Grant ROl DK34793-05 and is an Established Investigator of the American Heart Association. The author collaborates with the School of Health Sciences of the University of Crete.

Rscruited

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Hemodynamic perturbations. Sustained Inflammation, Progreswe scIeros~s. End Stage Nephropathy

Fig. 2

Antibody or cell mediated immune injury results in enhanced synthesis of bioactive mediator molecules either by the injured renal parenchymal cell (glomerular, tubulointerstitial) or by recruited cells such as neutrophiles, monocytes and platelets. Mediators identified to date include the various eicosanoids, growth factors (i.e. platelet-derived growth factor) and the cytokines (i.e. interleukins, tumor necrosis factor). Interactive associations may exist among these mediators, in that eicosanoid synthesis is stimulated by growth factors and cytokines and eicosanoids may modulate the synthesis of the latter. Eicosanoids either individually or in syngerism with other bioactive mediators can

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