Kidney International, Vol. 55 (1999), pp. 1672–1682

PERSPECTIVES IN BASIC SCIENCE

Potential role of platelet activating factor in acute renal failure

JOSE M. LOPEZ-NOVOA

Instituto Reina Sofıa de Investigacion Nefrologica, Departamento de Fisiologıa y Farmacologıa,Universidad de Salamanca, Salamanca, Spain

Potential role of platelet activating factor in acute renal failure. (Kf), and (c) tubular necrosis with the subsequent tubu-The clinical condition of acute renal failure (ARF) can be lar obstruction and fluid backleak [1]. Several researchcaused by a diverse number of renal injuries, but it is generally teams have studied the active renal vasoconstriction as-characterized by a sharp reduction in the glomerular filtration

sociated with renal failure, although a fully satisfactoryrate (GFR). A lipid mediator, platelet activating factor (PAF),explanation has not yet been found. One of the mostmay be one of the entities responsible for causing the hemody-

namic changes in the ARF kidney because it can act as a vaso- attractive research fields is the search for a factor(s)dilator or vasoconstrictor, depending upon its concentration. locally released into the kidney that could be responsibleThis review examines the action and mechanisms of PAF in for the alterations observed.experimental animal models of ischemia and nephrotoxicity, as

Acetylated alkyl phosphoglycerides constitute a newwell as renal failure associated with extrarenal diseases. Whileclass of lipid mediators with a wide spectrum of biologicalfurther research is necessary before extrapolating our current

knowledge of PAF into the prevention of renal failure or thera- activities. The first mediator of this class identified was apeutic intervention using PAF antagonists in human ARF, there product released from antigen-activated, IgE-sensitizedis reasonable evidence to support its role as a mediator of the

rabbit basophils with a potent effect in aggregating anddecrease in GFR characteristic of ARF.degranulating rabbit platelets [2]. Its name, “platelet-activating factor” (PAF), was derived from this activity.

Acute renal failure (ARF) is a clinical entity character- The chemical structure of PAF is 1-O-alkyl-2-acetyl-sn-ized by a sharp reduction in the glomerular filtration rate glyceryl phosphocholine [3]. Because of its structural(GFR). ARF can result from a variety of renal injuries, definition, PAF has been also termed PAF-acether orsuch as intoxication by heavy metals, organic solvents, AGEPC [2]. It has been demonstrated that PAF can beand drugs; renal ischemia after major vascular surgery; released not only by basophils but also by several othersevere bleeding; or obstetric surgery. ARF can also result cell types and organs, including the kidney. PAF has afrom immunological glomerular injury, although this ex- wide spectrum of diverse and potent biological activitiestremely important cause of renal failure is beyond of the that have been recently reviewed in several articles [4–6].scope of this review. The physiopathology of each type of Its effects on renal function make it an appropriate candi-renal injury has been extensively studied by developing date as a mediator of the reduction if GFR and RBFexperimental models that mimic the circumstances of associated with renal failure of different etiologies.the clinical condition. These models have differences in This article reviews the role of PAF in the genesis andboth the time sequence of renal events as well as the maintenance of ARF.relative importance of each event. In all of the experi-mental models developed thus far, there are several pro-

PLATELET-ACTIVATING FACTORcesses that seem to make a major contribution to theAND THE KIDNEYreduction in GFR characteristic of ARF. Among them,

the most important are (a) a reduction in renal blood flow Renal effects of platelet-activating(RBF) secondary to increased renal vascular resistance factor administration(RVR), (b) a decrease in the ultrafiltration coefficient When injected into a systemic vein, PAF induces a

decrease in RBF, GFR, and urinary flow. These effectsare secondary to a marked decrease in arterial pressureKey words: glomerular filtration rate, renal injury, PAF, acetylated alkyl

phosphoglycerides, hemodynamics. [7–11]. PAF-induced hypotension has been found to beassociated with plasma extravasation into the interstitialReceived for publication April 21, 1998compartment [7], as well as with a fall in cardiac outputand in revised form July 2, 1998

Accepted for publication July 6, 1998 caused by the direct effect of PAF on the coronary arter-ies [8, 10]. Infusion of PAF directly into the renal artery 1999 by the International Society of Nephrology

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Lopez-Novoa: PAF and ARF 1673

in dogs and rats results in a dose-dependent decrease in represented in Figure 1. A major substrate for PAF syn-thesis is the phospholipid 1-O-alkyl-2-acyl glycerophos-GFR, RBF, and urine flow or sodium excretion, withphocholine (alkylacylglycerophosphocholine), which givesno significant changes in systemic hemodynamics. Thus,rise to 1-O-alkyl-glycerophosphocholine, called lyso-Santos et al infused PAF continuously in the renal arteryPAF, through the action of membrane phospholipaseof dogs to achieve renal arterial blood concentrationsA2. Lyso-PAF can be the substrate of either a CoA-ranging between 1028 and 1025 m, and they observed adependent acyl transferase, giving rise again to the phos-dose-dependent decrease in RBF and GFR [12]. Badrpholipid 1-O-alkyl-2-acyl glycerophosphocholine, or aet al infused PAF into the renal artery of anesthetizedspecific CoA-dependent acetyl transferase, giving riserats at doses between 12.5 and 50 ng · kg21 · min21, andto the active molecule 1-O-alkyl-2-acetyl-sn-glycero-3-they observed a dose-dependent reduction of RBF andphosphocholine (PAF). PAF can be metabolized to lyso-

GFR [13]. Similar results were also obtained by Yoo,PAF by an acetyl hydrolase [21]. An alternative metabolic

Schlondorf and Neugarten in rats [14]. In addition, the route of PAF synthesis described in several biologicalPAF receptor antagonist SKF 96148 prevented these systems is catalyzed by a choline phosphotransferase thateffects of PAF infusion [14]. However, Handa et al have uses cytidine 59-diphosphate (CDP) choline and 1-O-alkyl-reported that the infusion of PAF as a bolus (5 to 10 2-acetyl-sn glycerol (alkylacetylglycerol) as substrate [22].ng · kg21) into the renal artery of rats produces a dose- Pirotzky et al observed that perfused rat kidneys re-dependent increase in RBF, which was abolished by the lease PAF after adding the calcium ionophore A23187 toPAF receptor antagonist L-659,989 [15]. In isolated per- the perfusion medium or after perfusion with an alkalinefused rat kidneys, PAF, at concentrations between 1028 medium [23]. It has been suggested that the release of

PAF by the isolated kidney in response to the calciumand 1025 m, causes a dose-dependent decrease in RVRionophore A23187 is not linked to the production of[16], but a decrease in GFR [17].renal prostaglandins [24]. Renomedullary kidney cellsA possible explanation for these apparent discrepanc-also produce significant amounts of PAF after incubationies can be found in the work of Juncos et al [18]. Thesewith ionophore A23187 [25]. The glomeruli are also ableauthors studied the direct effect of PAF on isolated mi-to synthesize and release considerable amounts of PAFcroperfused rabbit glomerular afferent arterioles. At na-[26]. Although endothelial cells are able to produce sig-nomolar concentrations, PAF caused a dose-dependentnificant amounts of PAF, the major source of glomerularconstriction of afferent arterioles. This constriction wasPAF seems to be the mesangium, as cultured mesangialblunted by cyclooxygenase inhibition but was enhancedcells synthesize high amounts of PAF, both in basal con-by nitric oxide (NO) inhibition. When arterioles wereditions and after activation [26]. Moreover, incubation

preconstricted with norepinephrine, picomolar concen- of mesangial cells with PAF induces de novo PAF synthe-trations of PAF (lower than those causing vasoconstric- sis by these cells. No PAF synthesis by cultured glomeru-tion) produced a dose-dependent vasodilation that was lar epithelial cells or by tubular cells has been observed,unaffected by cyclooxygenase inhibition but was abol- and their inability to synthesize PAF seems to be dueished by NO synthesis inhibition. This study strongly to the absence of acetyl-transferase activity in these cellssuggests that PAF exerts a receptor-mediated biphasic [27]. The mechanisms of increased PAF synthesis andeffect on afferent arterioles, dilating them (if previously release by mesangial cells in response to ischemia/anoxiaconstricted) at low concentrations and constricting them or toxic substances are represented in Figure 2.at higher concentrations. This study also suggests thatthe vasoconstrictor effect is mediated, at least in part,

PLATELET-ACTIVATING FACTOR ANDby cyclooxygenase products, whereas vasodilator activity EXPERIMENTAL MODELS OF ACUTEwould be mediated by NO. RENAL FAILURE

Considering both the effect of PAF on renal functionPlatelet-activating factor production by the kidneyand the ability of several kidney structures to synthesize

The renal origin of PAF was suggested by Caramelo and release PAF in response to several stimuli, PAF seemset al, who reported the presence of PAF in blood from to be a good candidate as a mediator of the hemodynamicnormal human and experimental animals, but not in blood and other renal alterations associated with ARF. Thefrom anephric patients or bilaterally nephrectomized an- development of reliable methods to measure PAF levelsimals [19]. In addition, Sanchez-Crespo et al found a in biological fluids [28] as well as the development ofPAF-like substance in the urine of normal subjects [20]. molecules that specifically block the binding of PAF to

All of the biochemical machinery necessary for the syn- its receptors [29, 30] has allowed researchers to evaluatethesis and degradation of PAF are present in the kidney. the importance of locally generated PAF in the physio-

pathology of renal failure. Table 1 reviews the studiesThe main metabolic pathways for PAF synthesis are

Lopez-Novoa: PAF and ARF1674

Fig. 1. Main enzymatic pathways responsiblefor the synthesis of PAF and its precursors.The numbers designate the following enzymes:1, alkyl-DHAP synthase; 2, NADPH:alkyl-DHAP oxidoreductase; 3, AcetylCoA:Alkyl-lysoglycerol-P acetyltransferase; 4, acyl-CoA:alkylglycero-P acyltransferase; 5, Alkylacetyl-glycerophosphate phosphohydrolase; 6, Alkyl-acylglycerophosphate phosphohydrolase; 7,CDPcholine: alkylacylglycerol cholinephospho-transferase; 8, DTT-insensitive: CDPcholine:alkylacetylglycerol cholinephosphotransferase;9, phospholipase A2; 10, CoA-independenttransacylase; and 11, acetylCoA:lysoPAF ace-tyl transferase.

in which treatment with PAF antagonists has improved Filep et al have also shown that after intestinal ischemiainduced by upper mesenteric artery ligation, PAF con-renal function in several experimental models of ARF.centration increases in the upper mesenteric vein [34].

Hemodynamically mediated renal failure In another experimental model of renal failure witha major hemodynamic component, that is, that inducedLopez-Farre et al have reported that glomeruli iso-

lated from rats undergoing a one-hour period of ischemia by intramuscular injection of glycerol, elevated glomeru-lar synthesis of PAF was also observed by Lopez-Farreshow increased PAF synthesis; this is supported by the

increased [3H]acetate incorporation to PAF [31] and by et al [35].The role of PAF in the genesis of ARF is furtherthe increased release of bioassayable PAF-like material

[32]. Moreover, these animals had a higher PAF concen- supported by the effects of PAF antagonists on thecourse of renal function in experimental models of thetration in the renal venous effluent [32]. The elevation

in blood PAF levels has also been shown in the ischemia disease. Thus, it has been reported that treatment withseveral PAF antagonists (Table 1) significantly protectsof other organs. Montrucchio et al have reported an

increased PAF release during the first minutes of reper- against the ARF induced by renal ischemia [31, 36–39].Kelly et al have suggested that the role of PAF in renalfusion after cardiac ischemia in the rabbit [33], while

Lopez-Novoa: PAF and ARF 1675

Table 1. PAF-antagonist treatment in experimental modelsof acute renal failure

Model PAF-antagonist Reference

Ischemia BA-52021 [31, 36, 37]Ischemia Alprazolam [31]Ischemia TVC 309 [38]Ischemia WEB 2086 [39]Ischemia Ro 24-476 [40]Glycerol BN-52021 [35, 43]Glycerol Alprazolam [35]Cyclosporine A BN-52021 [52]Cyclosporine A BN-52063 [51, 53]Gentamicin BN-52063 [58]Gentamicin BN-52021 [59, 60]Cisplatin BN-52063 [58]Cisplatin BN-52021 [59, 60]Kidney graft rejection RP-48740 [65]Kidney graft rejection WEB-2086 [66, 67]Kidney graft rejection SRI 63-441 [68]Pancreatitis BN-52021 [72]Endotoxemia L 653-150 [76]Endotoxemia L 652-731 [76]Endotoxemia BN-52021 [77]Endotoxemia SRI 63-675 [77]Endotoxemia BN-50739 [78]

In all of these studies, treatment with the PAF-antagonist increased the glo-merular filtration rate and/or renal blood flow.

Fig. 2. Mechanisms of increased platelet activating factor (PAF) syn-thesis in response to ischemia/anoxia or nephrotoxic substances in mes-angial cells. Ischemia and toxins impair oxidative metabolism, and in

The effects of PAF antagonist in ameliorating renalconsequence, cell adenosine 59-triphosphate (ATP) decreases, thus de-creasing the ability of the cells to re-uptake calcium into the sarcoplasmic failure have been also observed in ARF induced by intra-reticulum or pump calcium out of the cells. The increase in cytosolic muscular glycerol injection [35, 43].calcium activates calcium-dependent membrane phospholipase A2, which

It has been also demonstrated that endothelin playsacting on membrane 1-O-alkyl-2-acyl-glycerophosphocholine gives Lyso-PAF and a free fatty acid, frequently arachidonic acid, which in turn, a major role in GFR reduction after renal ischemia [44, 45]is transformed into eicosanoids by cyclooxygenases. Lyso-PAF is trans- and that this is mediated, at least in part, by PAF. Experi-formed in PAF by an acyl-transferase. PAF comes out of the cell and,

ments performed at our own laboratory have shown thatacting on specific receptors, increases cytosolic free calcium. No evidenceof the activation of the CDP-choline phosphotransferase pathway of endothelin induces the synthesis and release of PAFPAF synthesis in ischemia/anoxia or cell toxicity is currently available. from isolated glomeruli [46]. Other vasoconstrictor pep-

tides such as angiotensin II and vasopressin, also involvedin ARF, appear to stimulate PAF synthesis by endothe-lial cells [47]. PAF antagonists BN-52021 and WEB-2170injury after ischemia would be mediated by its effect onare able to partially block the contractile effects of endo-leukocyte–endothelial interactions [40]. This notion isthelin in cultured mesangial cells [46]. Data obtained atalso supported by the data of Riera et al, who showedour laboratory also show that endothelin-1 increases thethat in rat kidneys subjected to four hours of cold ische-release of a substance that shares chemical and biologicalmia and subsequent reperfusion with Krebs-Henseleitproperties with PAF from isolated rat glomeruli. More-solution containing 4.5% albumin with and without hu-over, endothelin-1 enhances the incorporation of acetateman polymorphonuclear neutrophils, the presence ofinto PAF both in isolated glomeruli [46] and culturedneutrophils in the perfusion solution produces a signifi-mesangial cells [48]. Both effects have a similar EC50,cant worsening of renal function [41]. In addition, thesuggesting that endothelin-1 induces PAF synthesiskidneys reperfused with neutrophils produced more PAFthrough the acetyl-transferase pathway [42]. Further sup-than those reperfused without neutrophils. Addition ofport for the involvement of endothelin and PAF in thethe PAF antagonist BN-52021 to the reperfusion fluidgenesis or maintenance of ischemic ARF is provided byincreased renal function in a dose-dependent mannerstudies showing that treatment with anti–ET-1 antibod-in comparison with kidneys perfused without BN-52021ies clearly improves the course of ischemic ARF and[41]. These results suggest that neutrophils contribute tosignificantly decreases the glomerular release of PAF inthe renal injury induced by ischemia reperfusion throughrats after one hour of renal ischemia [45].a mechanism that seems to be mediated by PAF release.

Another family of substances related to ischemia-reper-In addition, another PAF antagonist, TCV-309, reducesfusion events is reactive oxygen species (ROS) [49]. Stud-graft polymorphonuclear cell infiltration and enhances

renal function in kidneys with long, warm ischemia [42]. ies from our laboratory have shown that hydrogen perox-

Lopez-Novoa: PAF and ARF1676

ide induces mesangial cell contraction and myosin light- inhibited by incubation with the PAF antagonists BN-52021 and alprazolam. Furthermore, we have demon-chain phosphorylation, both effects being abolished by

the PAF-antagonist BN-52021 [50]. Hydrogen peroxide strated that mesangial cells incubated with gentamicinproduce higher amounts of PAF and eicosanoids thanalso stimulates PAF synthesis by mesangial cells [50].

These findings suggest that the possible effect of in- control cells through a mechanism mediated by the acti-vation of Ca-dependent phospholipase A2 [62].creased ROS production on mesangial cell contraction,

a major determinant of Kf reduction and hence GFR Cisplatin nephrotoxicity. Cisplatin is a valuable agentin oncologic therapy but has many adverse side-effects,decrease, may be mediated by ROS-stimulated synthesis

and release of PAF by the glomerular mesangium. nephrotoxicity being the most common and importantone. Cisplatin treatment in rats induces a nonoliguricAll of these data suggest that local PAF generation

in response to ischemia or secondary to other vasoactive ARF, with a marked decrease in GFR and RBF [63].Treatment with the PAF antagonists BN-52063 or BN-mediators plays a major role in the renal and intraglo-

merular hemodynamic alterations seen in experimental 25021 completely prevented the cisplatin-induced ARF,as all the parameters of renal function returned to normalmodels of ischemic ARF.values [58, 64].

Nephrotoxic acute renal failure Taken together, these results suggest that a major roleexists for local PAF release in the nephrotoxicity inducedCyclosporine A nephrotoxicity. Immunosuppressiveby a variety of drugs, such as aminoglycosides, cyclospo-therapy with cyclosporine is often associated with therine, and cisplatin.appearance of renal failure. A role for PAF as being

responsible for renal function derangement in animalsHyperacute xenogenic rejection of renal transplantstreated with cyclosporine has been inferred from differ-

ent types of experiments. In this sense, pretreatment The pathogenesis of hyperacute transplantation reac-tions includes the activation of a cascade of nonspecificwith the PAF antagonists BN-52021 or BN-52063 pre-

vented the decrease in GFR induced by cyclosporine inflammatory reactions that precipitate the destructionof target organs. In the case of the kidney, a sharp de-administration in rats [51–53]. Several mechanisms can

be invoked to explain the PAF-antagonist–induced ame- crease in GFR and the subsequent ARF is an early mani-festation of hyperacute rejection. PAF seems to representlioration of renal function after cyclosporine-induced re-

nal failure. First, the PAF antagonist L-659,989 signifi- an important component of these inflammatory cascades,and its role in mediating hyperacute kidney rejectioncantly reduces cyclosporine-induced afferent arteriole

constriction [54]. The PAF antagonist BN-50726 reduces comes from studies using PAF antagonists. Thus, inLewis rats that are receiving allogenic kidney transplantsrenal membrane peroxidation induced by cyclosporine

treatment in rats [55]. In addition, cyclosporine induces from Brown Norway rats, the PAF antagonist RP 48740delays accelerated kidney rejection [65]. Similar resultsmarked cell damage and reduced oxidative metabolism

in LLC-PK1 cells, a tubular cell line [56]. Two PAF antag- were observed with the PAF antagonist WEB 2086 [66].This PAF antagonist also markedly reduces eicosanoidsonists, PMS 536 and PMS 549 [56], prevent these effects.

Moreover, the contractile effect of cyclosporine on mes- and tumor necrosis factor-a (TNF-a) release after renalxenografting in pigs [67]. Furthermore, the PAF antago-angial cells can be prevented by coincubation with PAF

antagonists [57], and cyclosporine induces PAF synthesis nist SRI 63-441 prevents the acute rejection of cat-to-rabbit kidney xenografts and prolongs graft survival [68].and release by cultured rat mesangial cells [57].

Gentamicin nephrotoxicity. In other model of nephro- SRI 63-441 also inhibits hyperacute rejection of rat car-diac allografts by presensitized rat recipients, as well astoxicity with a major tubular component, such as genta-

micin-induced renal failure, PAF synthesis and release by guinea pig-to-rat and mouse-to-rat cardiac xenografts.In addition, a dramatic increase has been observed inthe kidney also seem to have an important pathogenic role.

Thus, Pavao dos Santos et al and Rodriguez-Barbero the production of a PAF-like substance by renal allografttissue undergoing untreated hyperacute rejection [69].et al have demonstrated that both tubular damage and

the reduction in GFR induced by gentamicin treatment In a pioneer clinical, double-blind, randomized study[70], kidney donors were treated with BN-52021 (240in rats can be partially prevented by treatment with the

PAF antagonists BN-52021 and BN-52063 [58, 59]. Im- mg, i.v.) or placebo just before kidney harvesting. Thekidneys were perfused and stored at 48C, adding BN-munoreactive PAF production is higher in glomeruli

from rats treated with gentamicin than in those from 52021 (0.08 mg/ml) or placebo to the preservation fluid.Recipients also received BN-52021 or placebo over thecontrol rats [60].

We have observed that gentamicin has a direct effect first four days after transplantation. After a minimumfollow-up of three months, the occurrence of post-trans-on mesangial cells, inducing cell contraction and an in-

crease in cytosolic-free calcium [61]. Both effects can be plant renal failure was significantly lower in the BN-

Lopez-Novoa: PAF and ARF 1677

52021 group (0 of 14) than in the placebo group (5 of MECHANISMS MEDIATING PLATELET-ACTIVATING FACTOR–INDUCED15) [70].RENAL FAILUREAll of these data suggest that PAF synthesis and action

in the transplanted kidney suffering hyperacute rejection The mechanisms responsible for PAF-induced falls inplay an important role in mediating the immunologic GFR are not well known, but all of the available evidenceand hemodynamic events associated with renal failure suggests that one is dealing with a multifactorial phenom-secondary to graft rejection. enon. At least three mechanisms are involved: a direct

effect of PAF on RBF, an effect of PAF on Kf, and thestimulation by PAF of the release of other vasoactiveRENAL FAILURE ASSOCIATED WITHmediators. These mechanisms are depicted in Figure 3.EXTRARENAL DISEASES

Acute pancreatitis Platelet-activating factor–induced reduction in renalblood flowCourses of acute pancreatitis have profound hemody-

namic disturbances and renal failure. Some reports have Platelet-activating factor–induced decreases in GFRsuggested that PAF can also play a role as a mediator could be based on the decrease in RBF [12, 13]. Anof the pathophysiological alterations observed in certain explanation for this decrease is that PAF raises RVRexperimental models of pancreatitis. PAF is involved in due to a direct contractile effect on vascular smooththe development of acute pancreatitis induced by immu- muscle [9, 12, 83]. In fact, Juncos et al have demonstratednocomplex injection [71]. Treatment with PAF antago- a direct effect of PAF on contracting, isolated, microper-nists ameliorates the hemodynamic alterations associ- fused afferent arterioles [18]. Moreover, afferent arteri-ated with acute pancreatitis induced by retrograde ole contraction also decreases intracapillary hydrostaticinjection of sodium deoxycholate [72]. Specifically, treat- pressure, which is the major force responsible for glomer-ment with BN-52021 prevented the sharp decrease in ular ultrafiltration. Another mechanism responsible forRBF associated with this model of acute pancreatitis [72]. PAF-induced decreases in GFR is that PAF causes aIn addition, PAF also seems to be involved in chronic decrease in plasma volume, caused by plasma extravasa-pancreatitis induced by bile duct ligation in the rat [73]. tion toward the interstitial compartment [84], with subse-Moreover, PAF administration to rabbits induces pan- quent activation of the sympathetic nervous system.creatitis [74], and long-term administration of PAF to However, the reduction in GFR induced by PAF infusionrats reduces both pancreatic regeneration and amylase can be observed in the absence of hypotension and hem-release [73]. An increase in pancreatic PAF levels has oconcentration [11–14]. Ins addition, PAF can also actalso been reported in animals with cerulein-induced pan- as a coinflammatory agent and increase microvascularcreatitis [75]. thrombosis and vascular obstruction, thus reducing RBF

and GFR [4, 5].Endotoxemic acute renal failure

Platelet-activating factor–induced decrease in theEndotoxemia and endotoxemic shock are associatedultrafiltration coefficientwith a sharp decrease in GFR and renal failure. Wang

and Dunn have demonstrated that treatment with PAF A decreased Kf has been suggested to play a role inantagonists such as L 653-150 and L 652-731 significantly several models of ARF. It should be noted that PAFprevents the decrease in GFR and RBF induced by the infusion in rats induces a decrease in GFR, RBF, and Kfinjection of endotoxin in rats [76]. Tolins et al have also [13]. The ARF induced by cyclosporine [51], cisplatin [58],observed that the PAF-antagonists BN-52021 and SRI or gentamicin [58, 85, 86] is associated with marked de-63-675 prevent the fall in GFR, RBF, and urinary flow crease in Kf as measured by micropuncture techniques.associated with endotoxin infusion in the rat [77]. Similar In these models, treatment with the PAF antagonistsobservations were reported by Rabinovici et al using BN-52021 or BN-52063 reversed the drug-induced de-BN-50739 [78]. Dobrowsky et al and Mozes et al have crease in Kf [51, 58].demonstrated increased blood levels of PAF after endo- In isolated rat glomeruli, Sharma et al have recentlytoxin injection in pigs [79, 80], whereas Morell et al described that PAF reduces glomerular capillary hydraulichave reported a dose- and time-dependent stimulation of conductivity (a major component of Kf) and albumin per-glomerular PAF production by lipopolysaccharide [81]. meability [87]. Some authors have suggested that mesan-Chang et al have reported increased renal PAF levels gial cell contraction and the subsequent glomerular con-after endotoxin administration [82]. traction reduce the glomerular filtration surface and Kf

All these data suggest that lipopolysaccharide-stimu- [88]. PAF is able to contract both isolated glomeruli [89]lated renal PAF production plays a major role in reduc- and cultured mesangial cells [90, 91]. It should be noted

that substances that induce a decrease in Kf, such asing GFR during endotoxemia.

Lopez-Novoa: PAF and ARF1678

Fig. 3. Mechanisms of platelet activating fac-tor (PAF)-induced decrease in glomerular fil-tration rate (GFR). The numbers in parenthe-ses are the citations reporting these effects.Plus and minus signs represent increase anddecrease, respectively.

cyclosporine or gentamicin, also induce mesangial cell con- Histamine. Another vasoactive substance released bythe perfused kidney in response to PAF is histamine [94].traction. Incubation with the PAF antagonists BN-52021

or alprazolam [57, 61] can prevent this contraction. When isolated rat kidneys are stimulated with calciumionophore A23187, kidneys release both PAF and hista-

Release of other vasoactive mediators mine [23]. Furthermore, guinea pig kidneys also releaseCyclooxygenase products. In isolated perfused rabbit PAF and histamine after an antigenic shock induced by

kidney [92], rat kidney [13, 14], and isolated rat glomeruli ovalbumin administration [95]. The PAF-receptor antag-[93], PAF administration increases the production of onist BN-52021 is able to antagonize histamine releasethromboxane B2 (TxB2), the stable metabolite of throm- by isolated kidneys subjected to antigenic shock in aboxane A2 (TxA2), a potent vasoconstrictor. Also, in concentration-dependent way [95]. Histamine, infusedcultured rat and human mesangial cells, PAF induces a directly into the renal artery, causes decreases in RVRdose-dependent stimulation of TxB2 and prostaglandin and increases in RBF, without significant changes inE2 (PGE2) release that can be specifically blocked by the mean arterial blood pressure and GFR, thus reducingPAF antagonists Kadsurenone or BN-52021 (abstract; glomerular filtration coefficient [96, 97]. Glomeruli areStork et al, Kidney Int 27:267A, 1985). In rats, the de- the major sites of histamine synthesis in the kidney [97],crease in GFR and RBF observed in response to intrare- and histamine induces a dose-dependent contraction ofnal PAF infusion was abolished in the presence of the isolated rat glomeruli and cultured rat mesangial cellscyclooxygenase inhibitors indomethacin and ibuprofen [98]. Thus, if glomerular cells in response to PAF release[13, 14]. Moreover, when administered concomitantly histamine and histamine induces mesangial cell contrac-with a TxA2 receptor antagonist, PAF led to significant tion, histamine could mediate at least a part of the glo-increases in GFR and RBF [13]. PAF-induced mesangial merular actions of PAF.cell contraction increases if prostaglandin synthesis isblocked and is partially reversed by the addition of PGE2

MECHANISMS UNDERLYING PLATELET-(abstract; Stork et al, ibid). The PAF-induced increasesACTIVATING FACTOR–INDUCEDin GFR and RBF when PAF is administered simultane-CELL CONTRACTIONously with a TxA2 receptor antagonists can be explained

As mentioned earlier in this article, the mechanismsby the vasodilator effect of both PGE2 and NO releasedunderlying PAF-induced reductions in GFR and RBFin response to PAF.

These results suggest that glomerular eicosanoid pro- are based on the contractile effect of PAF on both mes-angial and vascular smooth muscle cells. The cellularduction in response to PAF could regulate PAF-induced

changes in renal function. mechanisms responsible for cell contraction are appar-

Lopez-Novoa: PAF and ARF 1679

ently similar in both vascular smooth muscle cells and those reported for other vasoconstrictor substances suchas angiotensin II, endothelin, arginine vasopressin (AVP),in mesangial cells. First, the effect of PAF on cell contrac-

tion is mediated by the specific binding of this molecule or serotonin.to its receptors, as contraction is completely preventedby preincubation with either of the PAF-acether receptor

CONCLUSIONantagonists L652,731 or BN-52021 [86]. These PAF re-

This review provides reasonable experimental evi-ceptors have been studied in depth [99] and have beendence to support the role of PAF as a mediator of reduc-cloned by functional expression by Honda et al [100].tions in GFR in several models of experimental ARF ofHydropathy analysis of these receptors revealed sevenischemic or toxic origin. The involvement of PAF inputative transmembrane segments that are now recog-renal failure associated with glomerular immune diseasenized as a characteristic feature of G-protein–coupledhas been also demonstrated elsewhere, although thisreceptors. There is a total of 12 tyrosine residues thattopic is beyond the scope of this review. None of theare candidate substrates for tyrosine kinases: six in thestudies performed in experimental animals can be ex-cytoplasmic tail and two in each of the cytoplasmic loopstrapolated directly to clinical ARF, and further research[99]. Several asparagine residues are present at the exter-into this topic is undoubtedly needed. However, our cur-nal surface of the receptor and can serve as sites forrent understanding of the mechanisms controlling theattachment of glycosylated residues.release and actions of PAF, although incomplete, shouldIt has been reported that the interaction between PAFfinally provide the scientific basis for the preventive andand its receptor activates several transmembrane signalingtherapeutical use of PAF antagonists and other drugsmechanisms. For example, PAF activates phospholipase C,able to modify PAF synthesis in human ARF.phospholipase A2, and phospholipase D, protein kinase C,

and tyrosine kinase [99]. G proteins have been implicatedACKNOWLEDGMENTSin these types of activations. These effects and the second

messengers involved in smooth muscle or mesangial cell Grants from DGICYT (PM/88-0013, SAF 92/0039, and SAFT 95/0533) and an award from the Inigo Alvarez de Toledo Foundationactivation are discussed later in this article.supported the author’s works mentioned in this review. I thank Dr.

Different studies have suggested a role for Ca21 in Alejandro Esteller and Dr. Nelida Eleno for their helpful discussionand critique of the manuscript. Thanks are also due to N. Skinner ofPAF-acether–induced mesangial cell contraction [101,the Foreign Languages Translation Service, University of Salamanca,102], as it has been shown for other vasoconstrictor sub-for proofreading of the manuscript.

stances. PAF-acether induces a concentration-dependentincrease in cytosolic free calcium ([Ca21]i). The PAF- Reprint requests to Dr. Jose M. Lopez-Novoa, Departamento de

Fisiologıa y Farmacologıa, Universidad de Salamanca, Edificio De-acether–receptor antagonist BN-52021 blocks this effectpartamental, Campus Unamuno, 37007 Salamanca, Spain.

as well as PAF-induced mesangial cell contraction. E-mail: jmlnovoa@gugu.usal.esThe increase in [Ca21]i is mediated by phospholipase

C activation, which hydrolyzes phospatidylinositol-4,5- REFERENCESbisphosphate (PIP2) to generate inositol triphosphate (IP3) 1. Hostetter TH, Brenner BM: Renal circulatory and nephronand diglycerides (DG). This is supported by the observa- function in experimental acute renal failure, in Acute Renal Fail-

ure (2nd ed), edited by Brenner BM, Lazarus JM, New York,tions of Bonventre, Weber and Gronich [102] and KesterChurchill, 1988, pp 67–89et al [103] that PAF-acether induces a rapid increase in

2. Benveniste J, Henson PM, Cochianel G: Leukocyte dependentdiacylglycerol and IP3 in parallel to the PAF-induced histamine release from rabbit platelets: The role of PGE, baso-

phils and a platelet-activating factor. J Exp Med 136:1356–1377,increase in [Ca21]i. In turn, IP3 induces the release of Ca21

1972from intracellular stores, whereas DG activates protein3. Demopoulos CA, Pinckard RN, Hanahan DJ: Platelet-activat-

kinase C. Recently, it has been described that PAF can ing factor: Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-3-phospho-choline as the active components. J Biol Chem 254:9355–9358,also stimulate phospholipase D and diglyceride kinase,1979thus giving rise to further amounts of DG and also phos-

4. Camussi G: Potential role of platelet activating factor in renalphatidic acid (PA) [104]. PA has been described to act pathophysiology. Kidney Int 29:469–477, 1986

5. Schlondorff D, Neuwirth R: Platelet-activating factor and theas a lipid signal, augmenting or sustaining PAF signalkidney. Am J Physiol 251:F1–F11, 1986transduction. Thus, exogenous application of PA, like

6. Evans RD, Lund P, Williamson DH: Platelet-activating factorPAF, elevates [Ca21]i and increases inositol phosphate and its metabolic effects. Prostaglandins Leukot Essent Fatty

Acids 44:1–10, 1991production through activation of PLC [102]. The role of7. Bessin P, Bonnet J, Apffel D, Soulard C, Desgroux L, Pelasthe de novo synthesis of PA could also be to replenish

I, Benveniste J: Acute circulatory collapse caused by plateletthe PIP2 pool, which is hydrolyzed by PLC and PLA2 activating factor (PAF-acether) in dogs. Eur J Pharmacol 86:403–

413, 1983activities [105].8. Feuerstein G, Boyd LM, Ezra D, Goldstein RE: Effect ofIn view of the foregoing, the biochemical mechanisms

platelet activating factor on coronary circulation of the domesticresponsible for smooth muscle and mesangial cell con- pig. Am J Physiol 246:H466–H471, 1984

9. Humphrey DM, McManus LM, Satouchi K, Hanahan DJ,traction in response to PAF can be said to be similar to

Lopez-Novoa: PAF and ARF1680

Pinckard RN: Vasoactive properties of acetyl glyceryl ether phos- tagonists isolated from ginkgo biloba L: Chemistry, pharmacologyand clinical applications. Drugs Future 12:643–699, 1987phorylcholine and analogues. Lab Invest 46:422–427, 1982

10. Kenzora JL, Perez JE, Bergmann SR, Lange LG: Effects of 31. Lopez-Farre A, Ramon y Cajal S, Braquet P, Lopez-NovoaJM: Platelet-activating factor antagonists protect against post-acetyl glyceryl ether of phosphorylcholine (platelet activating fac-

tor) on ventricular preload, afterload and contractility in dogs. ischemic acute renal failure in rats. J Pharmacol Exp Ther253:328–333, 1990J Clin Invest 74:1193–1203, 1984

11. Hebert RL, Sirois P, Braquet P, Plante GE: Hemodynamic 32. Lopez-Farre A, Torralbo M, Lopez-Novoa JM: Enhanced pro-duction of PAF in glomeruli from rats after renal ischemia. Bio-effects of PAF-acether in the dog kidney. Prostaglandins Leukot

Med 26:189–202, 1987 chem Biophys Res Commun 152:129–135, 198833. Montrucchio G, Albatti G, Tetta C, De Luca R, Saunders12. Santos JC, Sanz E, Caramelo C, Lopez-Novoa JM: Effect of

intrarenal infusion of synthetic PAF-acether in dogs. Rev Esp RN, Emanuelli G, Camussi G: Release of platelet-activatingfactor from ischemic-reperfused rabbit heart. Am J PhysiolFisiol 44:273–278, 1988

13. Badr KF, Deboer DK, Takahashi K, Harris RC, Fogo A, Jacob- 256:H1236–H1246, 198934. Filep J, Herman F, Braquet P, Mozes T: Increased levels ofson HR: Glomerular responses to platelet-activating factor in the

rat: Role of thromboxane A2. Am J Physiol 256:F35–F43, 1989 platelet-activating factor in blood following intestinal ischemia inthe dog. Biochem Biophys Res Commun 158:353–359, 198914. Yoo J, Schlondorff D, Neugarten J: Thromboxane mediates

the renal hemodynamic effect of platelet activating factor. J Phar- 35. Lopez-Farre A, Gomez-Garre DN, Bernabeu F, Perez-Rod-rigo P, Ramon y Cajal S, Braquet P, Lopez-Novoa JM: Plateletmacol Exp Ther 253:743–748, 1990

15. Handa RK, Strandhoy JW, Buckalew VM Jr: Platelet activating activating factor mediates glycerol-induced acute renal failure inrats. Clin Sci 79:551–558, 1990factor is a vasodilator in the anesthetized rat. Am J Physiol

258:F1504–F1509, 1990 36. Plante GE, Sirois P, Braquet P: Platelet activating factor antago-nism with BN 52021 protects the kidney against acute ischemic16. Schwertschlag U, Scherf H, Gerber JG, Mathias M, Nies AS:

L-platelet activating factor induces changes on renal vascular injury. Prostaglandins Leukot Essent Fatty Acids 34:53–60, 198837. Torras J, Bordalba JR, Seron D, Moliner R, Carrera M,resistance, vascular reactivity and renin release in the isolated

perfused rat kidney. Circ Res 60:534–539, 1987 Valles J, Nartinez-Castelao A, Alsina J, Grino JM: Protectiveeffect of the PAF antagonist BN 52021 in an experimental renal17. Schwertschlag US, Dennis VW, Tucker JA, Camussi G: Non-

immunological alterations of glomerular filtration rate by s-PAF warm ischemia model. Transplant Int 6:236–238, 199338. Yin M, Kurvers HA, Buuman WA, Tangelder GJ, Boosterin the rat kidney. Kidney Int 34:779–785, 1988

18. Juncos JA, Ren YL, Arima S, Ito S: Vasodilator and constrictor MH, Daemen JH, Kondracki S, Koostra G: Beneficial effect ofplatelet-activating factor antagonist TCV-309 on renal ischemia-actions of platelet-activator factor in the isolated microperfused

afferent arteriole of the rabbit kidney: Role of endothelium- reperfusion injury. Transplant Proc 27:774–776, 199539. Gonzalez-Fajardo JA, Fernandez L, Alvarez T, Aguirre B,derived relaxing factor/nitric oxide and cyclooxygenase products.

J Clin Invest 91:1374–1379, 1993 Ramos G, Vaquero C: Protective effect of a platelet activatingfactor antagonist (WEB-2086) in postischemic renal failure. Ann19. Caramelo C, Fernandez-Gallardo S, Inarrea P, Santos JC,

Lopez-Novoa JM, Sanchez Crespo M: Presence of platelet acti- Vasc Surg 10:16–21, 196640. Kelly KJ, Tolkoff-Rubin NE, Rubin NH, Williams WW Jr,vating factor in blood from humans and experimental animals: Its

absence in anephric individuals. Biochem Biophys Res Commun Meehan SM, Meschter CL, Christenson JG, Bonventre JV:An oral platelet activating factor antagonist, Ro-24-476, protects120:789–796, 1984

20. Sanchez-Crespo M, Inarrea P, Alvarez V, Alonso F, Egido the rat kidney from ischemic injury. Am J Physiol 271:F1061–F1067, 1996J, Hernando L: Presence in normal urine of a hypotensive and

platelet activating phospholipid. Am J Physiol 244:F706–F711, 41. Riera M, Torras J, Herrero I, Valles J, Paubert-Braquet M,Cruzado JN, Alsina J, Grino JM: Neutrophils accentuate renal1983

21. Tselepis A, Pinckard NR: PAF-acetylhydrolase: A novel enzyme cold ischemia-reperfusion injury: Dose-dependent protective ef-fect of a platelet-activating factor receptor antagonist. J Pharma-with biochemical and clinical interest. Clin Chem Enzyme Com-

mun 4:279–290, 1992 col Exp Ther 280:786–794, 199742. Yin M, Buurman WA, Daemen JW, Kootstra G: The PAF22. Renooij W, Snyder F: Biosynthesis of 1-O-alkyl-2-acetyl-sn-gly-

cero-3-phosphocholine (platelet activating factor and hypotensive antagonist TCV-309 reduces graft PMN infiltration and enhancesearly function of 245-hour preserved rat kidneys with long warmlipid) by cholinephosphotransferase in various rat tissues. Bio-

chim Biophys Acta 663:545–556, 1981 ischemia. Transplantation 61:1443–1446, 199643. Homsi E, Oliveira-Dias EP, Gracia WE, Gontijo JA, Figueir-23. Pirotzky E, Bidault J, Burtin C, Gubler MC, Benveniste J:

Release of platelet activating factor, slow reacting substance and edo JF: Effects of nifedipine and platelet activating factor antago-nist (BN-52021) in glycerol-induced acute renal failure in rats.vasoactive amines from isolated rat kidneys. Kidney Int 25:404–

410, 1984 Renal Fail 18:883–892, 199644. Firth JD, Ratcliffe PJ, Raine AEG, Ledingham JGG: Endo-24. Nies AS, Tunney A, Barden A, Sturm MN, Vandongen R:

Release of platelet activating factor by the isolated rat kidney is thelin: An important factor in acute renal failure. Lancet 2:1179–1181, 1988not linked to the production of prostaglandins. J Pharmacol Exp

Ther 259:590–594, 1991 45. Lopez-Farre A, Gomez-Garre DN, Bernabeu F, Lopez-NovoaJM: A role for endothelin in the maintenance of postischemic25. Muirhead EM, Germain GS, Armstrong FB, Brooks B, Leach

BE, Byers LW, Pitcock JA, Brown P: Endocrine type antihyper- acute renal failure. J Physiol 444:513–522, 199146. Lopez-Farre A, Gomez-Garre DN, Bernabeu F, Montanes I,tensive function of renomedullary interstitial cells. Kidney Int

8:271–282, 1975 Millas I, Lopez-Novoa JM: Renal effects and mesangial cellcontraction induced by endothelin are mediated by PAF. Kidney26. Schlondorff D, Goldwasser P, Neuwirth R, Satriano JA,

Clay KL: Production of platelet activating factor in glomeruli Int 39:624–630, 199147. Camussi G, Aglietta M, Malavasi F, Tetta C, Piacibello W,and cultured mesangial cells. Am J Physiol 250:F1123–F1127, 1986

27. Pirotzki E, Ninio E, Bidault J, Pfister A, Benveniste J: Biosyn- Sanavio F, Bussolino F: The release of platelet-activating factorfrom human endothelial cells in culture. J Immunol 131:2397–thesis of platelet activating factor L. VI. Precursor of platelet-

activating factor and acetyl transferase activity in isolated rat 2403, 198348. Montero A, Rodriguez-Barbero A, Lopez-Novoa JM: A rolekidney cells. Lab Invest 5:567–572, 1984

28. Burgers JA, Akkerman J-WN: Measurement of platelet activat- for platelet activating factor in endothelin-1-induced mesangialcell proliferation. Eur J Pharmacol 243:235–240, 1993ing factor in biological specimens. J Lipid Med 3:241–248, 1991

29. Braquet P, Touqui L, Shen TY, Vargaftig BB: Perspectives in 49. Paller MS, Hoidal JR, Ferris TF: Oxygen free radicals in ische-mic acute renal failure in the rat. J Clin Invest 74:1156–1164, 1984platelet activating factor research. Pharmacol Rev 39:97–145, 1987

30. Braquet P: The ginkgolides, potent platelet activating factor an- 50. Duque I, Garcıa Escribano C, Rodriguez-Puyol D, Dıez-

Lopez-Novoa: PAF and ARF 1681

Marques ML, Lopez-Novoa JM, Arribas I, Hernando L, Rodri- 69. Mangino MJ, Anderson CB, Murphy MK, Turk J: Renal allo-graft platelet activating factor synthesis during acute cellular re-guez-Puyol D: Effects of reactive oxygen species on cultured rat

mesangial cells and isolated rat glomeruli. Am J Physiol 263:F466– jection. J Lipid Med 4:69–81, 199170. Grino JM: BN 52021: A platelet activating factor antagonist forF473, 1992

51. Santos OFP, Boim MA, Bregman R, Draibe SA, Barros EJG, preventing post-transplant renal failure. A double-blind, random-ized study. Ann Intern Med 121:345–347, 1994Pirotzky E, Schor N, Braquet P: Effect of platelet activating

factor antagonist on cyclosporin nephrotoxicity: Glomerular he- 71. Jancar S, DeGiaccobi G, Mariano M, Mencia-Huerta JM, Sir-ois P, Braquet P: Immune complex induced pancreatitis: Effectmodynamics evaluation. Transplantation 47:592–595, 1989

52. Pirotzky E, Colliez P, Guilmard C, Schaeverbeke J, Braquet of BN-52021, a selective antagonist of platelet activating factor.Prostaglandins 35:757–770, 1988P: Cyclosporine-induced nephrotoxicity: Preventive effect of a

PAF-acether antagonist, BN 52063. Transplant Proc 20(Suppl 72. Ais G, Lopez-Farre A, Gomez-Garre DN, Novo C, Romeo JM,Braquet P, Lopez-Novoa JM: Role of platelet-activating factor3):665–669, 1988

53. Bagnis C, Deray G, Dubois M, Pirotzky E, Jacquiaud C, Ba- in hemodynamic derangements in an acute rodent pancreaticmodel. Gastroenterology 102:181–187, 1991ghos W, Aupetit B, Braquet P, Jacobs C: Prevention of

cyclosporin nephrotoxicity with a platelet-activator factor antago- 73. Zhou W, Chao W, Levine BA, Olson MS: Evidence for plateletactivating factor as a late-phase mediator of chronic pancreatitisnist. Nephrol Dial Transplant 11:507–513, 1996

54. Lanese DM, Falk SA, Conger JD: Sequential agonist activation in the rat. Am J Pathol 137:1501–1508, 199074. Emmanuelli G, Motrucchio G, Gaia E, Dughera L, Corvetti G,and site-specific mediation of acute cyclosporin constriction in

rat renal arterioles. Transplantation 58:1373–1378, 1994 Gubetta L: Experimental acute pancreatitis induced by plateletactivating factor in rabbits. Am J Pathol 134:315–326, 198955. Massicot F, Warnet JM, Dutertre-Catella H, Martin C, Bra-

quet P, Claude JR: Protection against cyclosporin-induced neph- 75. Alonso R, Montero A, Arevalo MA, Garcıa LJ, Sanchez-Vicente C, Rodriguez-Nodal F, Lopez-Novoa JM, Calvo JJ:rotoxicity. 1. Effect off a PAF antagonist BN50276. J Lipid Med

Cell Signal 9:217–224, 1994 Platelet activating factor mediates pancreatic function derange-ment in caerulein-induced pancreatitis. Clin Sci 87:85–90, 199456. Massicot F, Lamouri A, Martin C, Pham-Huy C, Heymans F,

Warnet JM, Godfroid JJ, Claude JR: Preventive effects of two 76. Wang J, Dunn MJ: Platelet activating factor mediates endotoxin-induced acute renal failure in rats. Am J Physiol 253:F1283–F1289,PAF antagonists PMS 536 and PMS 549, on cyclosporin-induced

LLC-PK1 oxidative injury. J Lipid Med Cell Signal 15:203–214, 198777. Tolins JP, Vercellotti GM, Wilkowske M, Ha B, Jacob HS,1997

57. Rodriguez-Puyol D, Lamas S, Olivera A, Ortega G, Lopez- Raij L: Role of platelet activating factor in endotoxemic acuterenal failure in the male rat. J Lab Clin Med 113:316–324, 1989Farre A, Hernando L, Lopez-Novoa JM: Actions of cyclosporin

A on cultured rat mesangial cells. Kidney Int 35:632–638, 1989 78. Rabinovici R, Yue TL, Farhat M, Smith EF 3rd, Esser KM,Slivjak M, Feuerstein G: Platelet activating factor (PAF) and58. Pavao dos Santos OF, Boim M, Barros EJG, Schor N: Role of

platelet activating factor in gentamicin and cisplatin nephrotoxic- tumor necrosis factor-a (TNF-a) interactions in endotoxemicshock: Studies with BN 50739, a novel PAFG antagonist. J Phar-ity. Kidney Int 40:742–747, 1991

59. Rodriguez-Barbero A, Bosque E, Rivas-Cabanero L, Arevalo macol Exp Ther 255:256–263, 199079. Dobrowsky RT, Voyksner RD, Olson NC: Effect of SRI 63-M, Lopez-Novoa JM: Effect of platelet activating factor antago-

nist on gentamicin nephrotoxicity. Med Inflamm 1:23–26, 1992 675 on hemodynamics and blood PAF levels during porcine endo-toxemia. Am J Physiol 260:H1445–H1465, 199160. Rodriguez-Barbero A, Lopez-Novoa JM, Arevalo M: Role of

PAF in gentamicin-induced renal failure. Exp Nephrol 5:47–54, 80. Mozes T, Heiligers JPC, Tak CJ, Zijlstra FJ, Ben-Efraim S,Saxena PR, Bonta IL: Platelet activating factor is one of the1997

61. Rodriguez-Barbero AM, Rodriguez-Lopez R, Gonzalez-Sar- mediators involved in endotoxic shock in pigs. J Lipid Mediat3:309–325, 1991miento R, Lopez-Novoa JM: Gentamicin activates rat mesangial

cells: A role for platelet activating factor A. Kidney Int 47:1346– 81. Morell GP, Pirotzky E, Erard D, Desmottes RM, Bidault J,Damais C, Benveniste J: PAF-acether (platelet-activating factor)1353, 1995

62. Rodrıguez-Barbero A, Martınez-Salgado C, Rodrıguez- and interleukin-1-like cytokine production by lipopolysaccharide-stimulated glomeruli. Clin Immunol Immunopathol 46:396–405,Puyol D, Perez de Lema G, Lopez-Novoa JM: Involvement

of phospholipase A2 in gentamicin-induced rat mesangial cell 198882. Chang SW, Feddersen CO, Henson PM, Voelkel NF: Plateletactivation. Am J Physiol 273:F60–F66, 1997

63. Winston JA, Safirstein R: Reduced renal blood flow in early activating factor mediates hemodynamic changes and lung injuryin endotoxin-treated rats. J Clin Invest 79:1498–1509, 1987cisplatin-induced acute renal failure in the rat. Am J Physiol

249:F490–F496, 1985 83. Pinckard RN, McManus M, Hanahan DJ: Chemistry and biol-ogy of acetyl glyceryl ether phosphorylcholine (platelet-activating64. Pirotzky E, Guilmard C, Sidoti C, Ivanow F, Principe P, Bra-

quet P: Platelet activating factor antagonist, BN-52021 protects factor). Adv Inflamm Res 4:147–180, 198284. McManus LM, Pinckard RN, Fitzpatrick FA, O’Rourke RA,against cis-diamminedichloroplatinum nephrotoxicity in the rat.

Renal Fail 12:171–176, 1990 Crawford MH, Hanahan DJ: Acetyl glyceryl ether phosphorilcholine: Intravascular alterations following intravenous infusion65. Freiche JC, Lang J, Sedivy P, Touraine JL: Prolonged survival

of renal transplants in nonimmunized and hyperimmunized rats into the baboon. Lab Invest 45:303–307, 198185. Bayliss C, Rennke HG, Brenner BM: Mechanisms of the defectreceiving a platelet-activating factor antagonist. Transplantation

50:8–13, 1990 in glomerular ultrafiltration associated with gentamicin adminis-tration. Kidney Int 12:344–353, 197766. Bergmann R, Saumweber DM, Brecht HM, Hammaer C: Effects

of a PAF-antagonist (WEB 2086) on hyperacute xenogenic rejec- 86. Schor N, Ichikawa I, Rennke HG, Troy JL, Brenner BM: Patho-physiology of altered glomerular function in aminoglycoside-tion in ex vivo perfused kidneys. Transplant Proc 22:2009–2010,

1990 treated rats. Kidney Int 19:288–296, 198187. Sharma R, Sharma M, Li JZ, McCarthy ET, Savin J: Direct effect67. Saumweber DM, Bergmann R, Gokel M, Hammer C: Hyperacute

rejection in an ex vivo model of renal xenografting: Role of the of platelet activating factor on glomerular capillary permeability.Kidney Blood Press Res 20:25–30, 1997mediator response and its pharmacological manipulation by the

specific platelet-activating factor antagonist WEB 2086BS. Trans- 88. Mene P, Simonson MJ, Dunn MS: Physiology of the mesangium.Physiol Rev 64:1347–1370, 1989plantation 57:358–363, 1994

68. Makowa L, Chapman FA, Cramer DV, Quian SG, Sun H, 89. Barrio V, Arriba G, Lopez-Novoa JM, Rodriguez-Puyol D:Atrial natriuretic peptide inhibits glomerular contraction inducedStarzl TE: Platelet-activating factor and hyperacute rejection:

The effect of a platelet-activating factor antagonist, SRI 63-441, by angiotensin II and platelet activating factor. Eur J Pharmacol135:93–97, 1987on rejection of xenografts and allografts in sensitized hosts. Trans-

plantation 50:359–365, 1990 90. Schlondorff D, Satriano JA, Hagege J, Perez J, Baud L: Effect

Lopez-Novoa: PAF and ARF1682

of Platelet Activating Factor and serum-treated zymosan on pros- mines on renal hemodynamics and function in the isolated per-fused canine kidney. J Pharmacol Exp Ther 198:661–667, 1976taglandin E2 synthesis, arachidonic acid release and contraction

98. Sedor JR, Abboud HE: Histamine modulates contraction andof cultured rat mesangial cells. J Clin Invest 73:1227–1231, 1984cyclic nucleotides in cultured rat mesangial cells: Differential ef-91. Olivera A, Caramelo C, Arriba G, Lamas S, Rodriguez-Puyolfects mediated by histamine H1 and H2 receptors. J Clin InvestD, Schrier RW, Rodriguez-Barbero A, Lopez Novoa JM: Effect75:1679–1689, 1985of atrial natriuretic factor and calcium antagonists on platelet

99. Shukla S: Platelet-activating factor receptors and signal transduc-activating factor-induced contraction and calcium mobilization intion mechanisms. FASEB J 6:2276–2301, 1992rat mesangial cells. J Cardiovasc Pharmacol 24:388–393, 1994 100. Honda Z, Nakamura M, Miki I, Minami M, Watanabe T, Seyama

92. Weisman SM, Felsen D, Vaughan ED: Platelet-activating factor Y, Okado H, Toh H, Ito K, Miyamoto T, Shimizu T: Cloningis a potent stimulus for renal prostaglandin synthesis: Possible functional expression of platelet activating factor receptor fromsignificance in unilateral ureteral ligation. J Pharmacol Exp Ther guinea pig lung. Nature 349:342–346, 1991235:10–15, 1985 101. Kester M, Mene P, Dubyak GR, Dunn MJ: Elevation of cytosolic

93. Badr KF, Deboer DK, Takahashi K, Harris RC, Fogo A, Jacob- free calcium by platelet activating factor in cultured rat mesangialson HR: Glomerular responses to platelet-activating factor in the cells. FASEB J 1:215–219, 1987

102. Bonventre JV, Weber PC, Gronich JH: PAF and PDGF increaserat: Role of thromboxane A2. Am J Physiol 256:F35–F43, 1989cytosolic [Ca21] and phospholipase activity in mesangial cells. Am94. Alessandri MG, Giovannini L, Mian M, Palla R, Gattai V,J Physiol 254:F87–F94, 1897Ciangherotti A, Bertelli A: PAF-induced histamine release in

103. Kester M, Thomas CP, Wang J, Dunn MJ: Platelet activatingthe isolated perfused rat kidney. Int J Tissue React 10:33–38, 1988factor stimulates multiple signaling pathways in cultured rat mes-95. Berti F, Rossoni G, Braquet P: Immune release of histamineangial cells. J Cell Physiol 153:244–255, 1992and other lipid mediators from guinea-pig isolated kidney. Agents 104. Kester M: Platelet-activating factor stimulates phosphatidic acid

Actions 30:301–306, 1990 formation in cultured rat mesangial cells: Roles of phospholipase96. Radke KJ, Selkurt EE, Willis LR: The role of histamine H1 D, diglyceride kinase, and de novo phospholipid synthesis. J Cell

and H2 receptors in the canine kidney. Renal Physiol 8:100–111, Physiol 156:317–325, 19931985 105. Qian Z, Drews LR: A novel mechanism for acetylcholine to

generate diacylglycerol in brain. J Biol Chem 265:3607–3610, 199097. Campbell WB, Itskovitz HD: Effect of histamine and antihista-