Synthesis of hydroxyeicosatetraenoic acids and leukotrienes in rat nephrotoxic serum glomerulonephritis. Role of anti-glomerular basement membrane antibody dose, complement, and neutrophiles.

Abstract

The basal and stimulated synthesis of immunoassayable 12-and 5-monohydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT) B4 and C4 was studied in glomeruli isolated from rats with nephrotoxic serum glomerulonephritis (NSGN) induced by low (30 ,g/g body weight) or high (105 ,g/g) doses of anti-rat glomerular basement membrane (GBM) immunoglobulin (Ig). In the early heterologous phase of the disease, low doses of anti-GBM Ig enhanced the basal synthesis of 12-HETE but not that of 5-HETE or LT. High anti-GBM Ig doses enhanced the basal synthesis of 5-HETE and LTB4 as well. Under stimulated conditions, enhanced glomerular production of 5-HETE and LTB4 occurred at 15 min after infusion of anti-GBM Ig, peaked at 1 h, and returned toward control levels by 24 h. At 48 h, 72 h, and on day 12, the synthesis of these eicosanoids was impaired. Neutrophile depletion only partially reduced glomerular eicosanoid synthesis after induction of NSGN whereas complement depletion significantly reduced 5-HETE, 12-HETE, and LTB4. These observations indicate that in the heterologous phase of NSGN there is enhanced but short-lived glomerular 5-HETE and LTB4 synthesis. This phenomenon is mediated by complement activation and may be an important proinflammatory event leading to capillary wall injury in the early stages of the disease.

Transfection of rat kidney with human 15-lipoxygenase suppresses inflammation and preserves function in experimental glomerulonephritis

“…Previous studies have shown that glomerular LTB 4 production peaks in the early phase of glomerulonephritis and has pro-inflammatory properties in this model (14,39). Fig.…”

“…Induction of pNTS leads to substantial acute reductions in the glomerular filtration rate (GFR) and renal plasma flow rate (RPF) (33,39,40). While these parameters were depressed to an equivalent degree in all animals Total urinary protein excretion rates͞day are shown in Fig.…”

Platelets and neutrophils are critical to the enhanced glomerular arachidonate metabolism in acute nephrotoxic nephritis in rats.

“…phenomenon (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). NTN and related models of immunemediated glomerulonephritis are characterized by glomerular inflammation, marked alterations in glomerular eicosanoid production, as well as glomerular dysfunction (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

“…NTN and related models of immunemediated glomerulonephritis are characterized by glomerular inflammation, marked alterations in glomerular eicosanoid production, as well as glomerular dysfunction (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). These alterations in glomerular eicosanoid production appear to be critically important to the pathophysiology of this disease model.…”

Predominant functional roles for thromboxane A2 and prostaglandin E2 during late nephrotoxic serum glomerulonephritis in the rat.

“…In previous studies, we (3) and others (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) have used a rat model of glomerulonephritis, induced by the administration ofrabbit anti-rat glomerular basement membrane (GBM) antibody (nephrotoxic serum [NTS]), to define the mechanisms underlying the reductions in GFR and the alterations in renal vascular tone which characterize glomerular inflammatory injury. Two phases of this disease model are recognized: an early (heterologous) phase, occurring 2-24 h after antibody binding to GBM with subsequent complement activation, neutrophil infiltration, and falls in GFR and RPF; and a more chronic (autologous) phase, observed by [7][8][9][10][11][12][13][14] d (19), characterized by proteinuria, a macrophage/monocyte cellular infiltrate, and proliferation of resident glomerular mesangial cells (18)(19)(20).…”