The Role of Platelet-Activating Factor in Mesangial Pathophysiology

Platelet-activating factor (PAF) is a powerful proinflammatory mediator that displays an exceedingly diverse spectrum of biological effects. Importantly, PAF is shown to participate in a broad range of pathologic conditions. This review focuses on the role that PAF plays specifically in the pathophysiology of the kidney, the organ that is both a source and a target of PAF. Renal mesangial cells are responsible for glomerular PAF generation and, ultimately, are the victims of its excessive production. Mesangial pathology is widely acknowledged to reflect glomerular damage, which culminates in glomerulosclerosis and proteinuria. Therefore, modulation of mesangial cell responses would offer a pathophysiology-based therapeutic approach to prevent glomerular injury. However, the currently available therapeutic modalities do not allow for targeted intervention into these processes. A more profound understanding of the mechanisms that govern PAF metabolism and signaling in mesangial cells is important, because it could facilitate the quest for improved therapies for renal patients on the basis of PAF as a drug target. Platelet-activating factor (PAF) is a powerful proinflammatory mediator that displays an exceedingly diverse spectrum of biological effects. Importantly, PAF is shown to participate in a broad range of pathologic conditions. This review focuses on the role that PAF plays specifically in the pathophysiology of the kidney, the organ that is both a source and a target of PAF. Renal mesangial cells are responsible for glomerular PAF generation and, ultimately, are the victims of its excessive production. Mesangial pathology is widely acknowledged to reflect glomerular damage, which culminates in glomerulosclerosis and proteinuria. Therefore, modulation of mesangial cell responses would offer a pathophysiology-based therapeutic approach to prevent glomerular injury. However, the currently available therapeutic modalities do not allow for targeted intervention into these processes. A more profound understanding of the mechanisms that govern PAF metabolism and signaling in mesangial cells is important, because it could facilitate the quest for improved therapies for renal patients on the basis of PAF as a drug target. A substantial body of literature is available on the role of platelet-activating factor (PAF) in renal pathophysiology. After the discovery of PAF by Jacques Benveniste,1Benveniste J. Henson P.M. Cochrane C.G. Leukocyte-dependent histamine release from rabbit platelets. The role of IgE, basophils, and a platelet-activating factor.J Exp Med. 1972; 136: 1356-1377Crossref PubMed Scopus (969) Google Scholar a publication burst in the field of PAF in kidney research was observed. We summarize previous findings and point out conflicting reports and information gaps to revive the research interest with this review. Taking into account the recently acknowledged central role of mesangial cells in many forms of glomerular injury and the identification of a gene that, when overexpressed in mesangial cells, leads to an increase in PAF and mesangial matrix expansion, we set the boundaries of this review to focus on the role of PAF in mesangial pathophysiology. PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a mediator of inflammation. By its chemical nature, PAF belongs to the ether phospholipids.2Vance D.E. Vance J.E. Biochemistry of Lipids, Lipoproteins, and Membranes.ed 4. Elsevier Science, New York2002Google Scholar Strictly speaking, PAF is not a single entity but rather a generic collective term for a heterogeneous class of molecular species with different saturated or mono-/di-unsaturated alkyl, acyl, or alkenyl chains attached through ether linkage at the sn-1 position of the glycerol backbone3McManus L.M. Woodard D.S. Deavers S.I. Pinckard R.N. PAF molecular heterogeneity: pathobiological implications.Lab Invest. 1993; 69: 639-650PubMed Google Scholar, 4Pinckard R.N. Woodard D.S. Showell H.J. Conklyn M.J. Novak M.J. McManus L.M. Structural and (patho)physiological diversity of PAF.Clin Rev Allergy. 1994; 12: 329-359Crossref PubMed Scopus (30) Google Scholar (Figure 1). The structural diversity translates into differences in biological potency, with the predominant and most biologically active species of PAF containing C16:0, C18:0, or C18:1 alkyl groups.4Pinckard R.N. Woodard D.S. Showell H.J. Conklyn M.J. Novak M.J. McManus L.M. Structural and (patho)physiological diversity of PAF.Clin Rev Allergy. 1994; 12: 329-359Crossref PubMed Scopus (30) Google Scholar, 5Schlondorff D. Goldwasser P. Neuwirth R. Satriano J.A. Clay K.L. Production of platelet-activating factor in glomeruli and cultured glomerular mesangial cells.Am J Physiol. 1986; 250: F1123-F1127PubMed Google Scholar PAF is a proinflammatory autacoid (a local hormone with paracrine effects) with pleiotropic effects. As a matter of fact, the term platelet-activating factor is a misnomer, because the effect of PAF on physiologic processes is not limited to and goes far beyond degranulation of platelets, the first effect that was documented.1Benveniste J. Henson P.M. Cochrane C.G. Leukocyte-dependent histamine release from rabbit platelets. The role of IgE, basophils, and a platelet-activating factor.J Exp Med. 1972; 136: 1356-1377Crossref PubMed Scopus (969) Google Scholar, 6Barbaro J.F. Zvaifler N.J. Antigen induced histamine release from platelets of rabbits producing homologous PCA antibody.Proc Soc Exp Biol Med. 1966; 122: 1245-1247Crossref PubMed Scopus (48) Google Scholar, 7Henson P.M. Activation of rabbit platelets by platelet-activating factor derived from IgE-sensitized basophils. Characteristics of the aggregation and its dissociation from secretion.J Clin Invest. 1977; 60: 481-490Crossref PubMed Scopus (62) Google Scholar Diverse biological activities are ascribed to PAF, and it was found to be involved in the pathogenesis of a wide range of diseases.8Feuerstein G. Rabinovici R. Leor J. Winkler J.D. Vonhof S. Platelet-activating factor and cardiac diseases: therapeutic potential for PAF inhibitors.J Lipid Mediat Cell Signal. 1997; 15: 255-284Crossref PubMed Scopus (29) Google Scholar, 9Goldstein R.E. Feuerstein G.Z. Bradley L.M. Stambouly J.J. Laurindo F.R. Davenport N.J. Cardiovascular effects of platelet-activating factor.Lipids. 1991; 26: 1250-1256Crossref PubMed Scopus (17) Google Scholar, 10Schlondorff D. Neuwirth R. Platelet-activating factor and the kidney.Am J Physiol. 1986; 251: F1-F11PubMed Google Scholar In addition to the effects of the structural variation, the broad spectrum of PAF effects is achieved through a broad range of downstream mediators (Figure 2), via which PAF can elicit many of the reactions of inflammation and allergy, including enhanced leukocyte adhesion, chemotaxis, leukocyte degranulation, respiratory burst, and increased vascular permeability.11Braquet P. Hosford D. Braquet M. Bourgain R. Bussolino F. Role of cytokines and platelet-activating factor in microvascular immune injury.Int Arch Allergy Appl Immunol. 1989; 88: 88-100Crossref PubMed Scopus (87) Google Scholar, 12Jancar S. Braquet P. Sirois P. Interactions of arachidonic acid metabolites and platelet activating factor and of in J Biol Google Scholar, M. F. J. Platelet-activating factor in and from and the by and but not from Google Scholar A of cell as and renal mesangial cells, are shown to PAF, which can be via the and the D.E. Vance J.E. Biochemistry of Lipids, Lipoproteins, and Membranes.ed 4. Elsevier Science, New York2002Google Scholar, F. of platelet-activating factor and Exp PubMed Google Scholar, F. of platelet activating factor and ether and Clin Biol Google Scholar The a structural of in which the of a biologically which is and leads to the of of of mesangial PubMed Scopus Google Scholar, D. S. R. A single both platelet-activating factor and of and of Biol PubMed Scopus Google Scholar (Figure In the PAF from as in F. of the for the of platelet-activating factor (PAF) via in cells with PAF Biol PubMed Google Scholar, F. the in the of platelet-activating 1997; PubMed Scopus Google Scholar, D.S. F. The in the of platelet-activating of a in from the renal of Biol PubMed Google Scholar (Figure PAF is as a because it is to biologically by and M. platelet activating Lipid PubMed Scopus Google Scholar, platelet-activating factor PubMed Scopus Google Scholar, Platelet-activating factor in and PubMed Scopus Google Scholar This is by the that PAF at a as as a of in the of M. M. S. of platelet-activating factor of cells.Am J PubMed Scopus Google Scholar in However, it is the from is of its or to PAF mechanisms that and R.N. Woodard D.S. Showell H.J. Conklyn M.J. Novak M.J. McManus L.M. Structural and (patho)physiological diversity of PAF.Clin Rev Allergy. 1994; 12: 329-359Crossref PubMed Scopus (30) Google Scholar cell are to PAF, the kidney is an important, not source of PAF in the body because PAF is in the of patients and that S. D. P. M. of platelet-activating factor in from and in PubMed Scopus Google Scholar This is by the of PAF release by the J. J. of platelet-activating and from PubMed Scopus Google Scholar of the for PAF are in the of PAF as D. Goldwasser P. Neuwirth R. Satriano J.A. Clay K.L. Production of platelet-activating factor in glomeruli and cultured glomerular mesangial cells.Am J Physiol. 1986; 250: F1123-F1127PubMed Google Scholar, in and renal J PubMed Scopus Google Scholar of the and D.S. F. The in the of platelet-activating of a in from the renal of Biol PubMed Google Scholar of the is found in renal Production of PAF in the kidney can be to cells and renal of the is because increased PAF is in and S. R. R. J.J. J. of platelet-activating factor in and PubMed Scopus Google Scholar, S. M. J.J. J. A the glomerular of mediators and in Exp Immunol. PubMed Scopus (17) Google Scholar forms of renal glomerular leukocyte the renal cell glomerular mesangial and cells can PAF. PAF is in the and its are found to be in renal patients and with S. R. R. J.J. 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Platelet-activating factor PubMed Scopus Google Scholar In the kidney, is is a of its the in the renal with a in the by the the the the by the with the of platelet activating factor the PubMed Scopus Google Scholar In a and the of gene in this and M. S. Activation of platelet-activating factor renal inflammation and Invest. PubMed Scopus Google Scholar is the to species of the PAF class of PAF renal and glomerular in in and proteinuria. the effect of PAF is different the renal vascular be species In the PAF renal to a in glomerular and renal of PAF into the renal these effects of this effect is to be and not to Platelet-activating factor is a renal in the J Physiol. Google Scholar, of responses by platelet-activating factor in kidney.Am J Physiol. 1991; Google Scholar in the kidney However, in the PAF renal and effect on the of the and rabbit D. Neuwirth R. 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Platelet-activating factor gene and of matrix in cultured and mesangial role of Soc 1997; PubMed Google Scholar the effect is on and the of the was by the increased production. the of the matrix PAF the of and of the Therefore, the molecular through which PAF participate in the mesangial matrix glomerular injury is to be by In with these in found mesangial matrix in to be with a gene for an that of which be for PAF M. P. R. of mesangial matrix in and identification of as a Soc PubMed Scopus (17) Google Scholar not the PAF and mesangial matrix but potential research that to and of the PAF is widely as a many of glomerular as mesangial expansion, and are on the PAF and mesangial cell PAF not in cultured mesangial M. R. D. J. Platelet-activating factor gene and of matrix in cultured and mesangial role of Soc 1997; PubMed Google Scholar, S. J.F. Platelet-activating factor (PAF) increase by both and in mesangial Clin Med. 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The mesangial cell cell is an Soc PubMed Scopus Google Scholar PAF be of the cytokines by mesangial cells that with R. S. R. G. mesangial cells to platelet-activating factor that in cultured PubMed Scopus (48) Google Scholar The of the PAF and the of therapeutic are on the are that can or PAF from its are in the of and Platelet-activating factor a review of its role in and of PAF in the Allergy PubMed Scopus Google Scholar but in for G. G. G. Role of platelet-activating factor in PubMed Scopus Google Scholar G. P. Platelet-activating factor the cell and in J PubMed Scopus Google Scholar and kidney injury. with the in a of mesangial cell injury the in and structural in F. G. The platelet activating factor glomerular and in a of mesangial cell Soc 1991; PubMed Google Scholar The was recently in a of with at the first leads to a in of and of the and M. S. Activation of platelet-activating factor renal inflammation and Invest. PubMed Scopus Google Scholar target for that is an increase in PAF the that the of active PAF. with PAF and vascular PAF G. S. of a platelet-activating factor PubMed Scopus Google Scholar shown effects in for R.N. platelet-activating factor in with and 26: PubMed Scopus Google Scholar S. effects of platelet-activating factor and on in PubMed Scopus Google Scholar R. D. M. G. M. D. P. P. gene of platelet-activating and in PubMed Scopus Google Scholar and J. J. G. S. G. platelet-activating factor the of in the PubMed Scopus Google Scholar but effects on the kidney are findings that increased is with mesangial matrix expansion, through increased PAF M. P. R. of mesangial matrix in and identification of as a Soc PubMed Scopus (17) Google Scholar the for this in which is are PAF in the pathogenesis of renal because of its effects on of kidney (Figure However, a role of PAF in physiologic processes not be and A of on the of PAF in the of renal pathophysiology to be The information gaps and in this review which and potential of the PAF in mesangial are PAF and and are the effects of PAF on the of mesangial and PAF these is of because it would intervention to that biological of PAF not be to an proinflammatory but it be involved in a of processes. Renal of the available and is because it into the role that PAF plays in the the structural of PAF molecular most limited to and species are the in the drug is PAF The biological and of the range of molecular of the PAF, as the in and of PAF species in and and its potential to be in because the of the PAF molecular the and of renal