Symposium on the Pathogenetic Mechanisms in Nephritis

Kidney International (1989) 35, 985–992; doi:10.1038/ki.1989.82

Eicosanoids and the modulation of glomerular immune injury

Elias A Lianos1

1Department of Medicine, Nephrology Division, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin, USA

Correspondence: Dr Elias A Lianos, Department of Medicine, Nephrology Division, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226, USA.

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Abstract

For the purposes of this review, glomerular immune injury is viewed as a process initiated at the level of glomerular structures following deposition and interaction of defined immunologic reactants which may activate the synthesis of proinflammatory mediators. Renal hemodynamic perturbations and glomerular capillary wall injury resulting in proteinuria are the most frequent sequelae. When glomerular injury is initiated by deposition of antibody with specificity against glomerular antigens (structural or trapped) or against non-renal soluble antigens, the ensuing reaction can be of an inflammatory or noninflammatory type. The former is frequently associated with intraglomerular complement activation, recruitment of neutrophils and platelets and recruitment or enhanced expression of sensitized monocytes-macrophages. In noninflammatory forms, capillary wall injury can be mediated by antibody deposition alone or it may require complement activation. Regardless the type of injury, activation of a number of proinflammatory mediator systems has been documented following glomerular deposition of immunologic reactants. The metabolic products formed following activation of these systems may mediate perturbations in renal hemodynamics and in the permeability of the glomerular capillary wall. Moreover, they may play a regulatory role on the function of endogenous glomerular or blood borne cells recruited in glomerular structures following initiation of injury. Table 1 summarizes the mediator systems which have been studied in various forms of experimental glomerulonephritis.

The use of powerful investigative tools such as tissue culture and analytical biochemistry has yielded an impressive amount of information regarding the biosynthetic capabilities of renal tissues. The renal glomerulus and its various cell types are now regarded as active sites of synthesis of lipid compounds with autacoid and proinflammatory effects. Of the compounds with proinflammatory effects, major emphasis has been placed on the biosynthesis and role of eicosanoids. Eicosanoids are oxygenated metabolites of arachidonic acid (eicosatetraenoic acid) and other polyunsaturated fatty acids which contain 20 carbons (eicosa indicates 20). These polyunsaturated fatty acids are derived from dietary "essential" fatty acids and are present in esterified form on membrane phosphoglycerides of most mammalian cells. The literature on eicosanoids has been expanding exponentially with approximately 10 publications now appearing daily, a substantial number of which pertain to the kidney.

The reader is, therefore, referred to a number of key references regarding the distribution of arachidonate on renal cell phospholipids [11], the release of arachidonate in response to cell-surface perturbations or receptor-mediated mechanisms [12], the renal compartmentalization of enzymes involved in the sequential conversion of arachidonate to prostaglandins (PG), thromboxanes (Tx) [13], the metabolites originating via the cytochrome P450-linked monooxygenase system [14] and the biosynthesis and proinflammatory role of arachidonate lipoxygenation products (hydroxyeicosatetraenoic acids, leukotrienes and lipoxins) [15, 16]. Eicosanoids exhibit a bewildering and often widely differing spectrum of biological activities with frequently opposing biological effects which may further depend on the species studied. At the risk of oversimplifying, this review will regard the renal effects of arachidonate cyclooxy-genation products (dienoic prostaglandins and thromboxanes) as being primarily vasoactive while those of arachidonate lipoxygenation products (hydroxyeicosatetraenoic acids and leukotrienes) as being mainly proinflammatory. Of additional relevance to this review is the role of eicosanoids on immuno-regulation [17] and their potential role in regulating glomerular cell function, which has primarily been explored in mesangial cells with respect to their contractile properties [18, 19].

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