Increased glomerular thromboxane synthesis as a possible cause of proteinuria in experimental nephrosis.

Remuzzi, Giuseppe; Imberti, Luisa; Rossini, M; Maurer-Morelli, Cláudia Vianna; Carminati, Claudia Elisa; Cattaneo, G; Bertani, Tullio

doi:10.1172/jci111703

Cited by 161 publications

(72 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was due, at least in part, to exaggerated production of thromboxane A 2 and activation of the thromboxane-prostanoid (TP) receptor. 6 These findings are consistent with older studies showing efficacy of thromboxane synthase inhibitors and TP receptor antagonists in experimental models such as adriamycin nephropathy 7 and murine lupus nephritis. 8 In this issue of JASN, Stitt-Cavanagh et al 9 implicate another prostanoid pathway in glomerular disease: Prostaglandin E 2 (PGE 2 ) acting through its EP4 receptor.…”

supporting

confidence: 87%

“…In this context, VEGFR1 is considered a modulatory receptor because it avidly binds VEGF but is phosphorylated only weakly. 6,7 Endothelial cells, in turn, secrete pro-survival mitogens, such as PDGF, to recruit support cells and aid their survival. Indeed, global deletion of either PDGF-␤ or its receptor results in rudimentary glomeruli lacking mesangial cells.…”

Section: Disclosuresmentioning

confidence: 99%

See 1 more Smart Citation

The EP4 Receptor for Prostaglandin E2 in Glomerular Disease

Sparks¹,

Coffman²

2010

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Prostanoids generated by the metabolism of arachidonic acid through the cyclooxygenase (COX) pathway have diverse functions in health and disease. 1 The kidney is prominent among the physiologic systems affected by these ubiquitous mediators. Along with effects to modulate renal blood flow, GFR, and sodium excretion, prostanoids affect the function of the glomerular filtration barrier. This is illustrated by clinical studies showing that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX enzymes, attenuate the levels of proteinuria in patients with glomerular diseases. 2,3 Because NSAIDs block production of all prostanoids, the specific prostanoids influencing glomerular function in this setting cannot be discerned. Moreover, because NSAIDs frequently cause adverse effects in patients with kidney disease, including acute deterioration in GFR and exacerbation of hypertension, this approach to antiproteinuric therapy has limited applications.In experimental models of glomerular disease, a number of studies have indicated beneficial effects of more specific pharmacologic inhibitors that block individual prostanoid synthetic pathways or receptors. More recently, this issue has been explored using modern molecular genetics. For example, Harris and associates 4,5 showed that overexpression of the inducible COX isoform, COX2, in podocytes of transgenic mice enhances susceptibility to glomerular injury caused by adriamycin or puromycin. This was due, at least in part, to exaggerated production of thromboxane A 2 and activation of the thromboxane-prostanoid (TP) receptor. 6 These findings are consistent with older studies showing efficacy of thromboxane synthase inhibitors and TP receptor antagonists in experimental models such as adriamycin nephropathy 7 and murine lupus nephritis. 8 In this issue of JASN, Stitt-Cavanagh et al. 9 implicate another prostanoid pathway in glomerular disease: Prostaglandin E 2 (PGE 2 ) acting through its EP4 receptor. This finding is surprising from at least two perspectives. First, in the studies of Harris and associates, deletion of EP4 receptors from podocytes had no effect on proteinuria and kidney injury in mice also overexpressing COX2. 6 Second, the EP4 receptor has long been considered to have beneficial and protective effects in kidney disease and hypertension.Once COX and PGE synthases form PGE 2 through the successive metabolism of arachidonic acid, it elicits its biological effects through a family of G protein-coupled receptors. These receptors, by convention designated EP (for E-prostanoid) receptors, are divided into four distinct pharmacologic classes: EP1 through 4. 10,11 The EP4 receptor signals through Gs proteins and adenylyl cyclase. 11 Because of the linkage between enhanced formation of cAMP and relaxation of bronchial and vascular smooth muscle, the EP4 receptor has been classically considered a relaxant receptor. 11 In the kidney, vasodilator actions of PGE 2 , likely mediated by the EP4 receptor, are linked to protection of renal blood flow during sta...

show abstract

supporting

confidence: 87%

Section: Disclosuresmentioning

confidence: 99%

The EP4 Receptor for Prostaglandin E2 in Glomerular Disease

Sparks¹,

Coffman²

2010

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Renal eicosanoid metabolism is enhanced in a number of renal pathologic states such as glomerulonephritis (12), adriamycin-induced nephrosis (13), acute renal failure (14), and hydronephrosis (15). Additionally, this metabolic alteration appears to have pathophysiologic significance in these conditions (12)(13)(14)(15).…”

mentioning

confidence: 99%

“…Additionally, this metabolic alteration appears to have pathophysiologic significance in these conditions (12)(13)(14)(15). In order to assess the potential role of LTB4 in renal inflammation, the capability of glomeruli to synthesize this eicosanoid was assessed.…”

mentioning

confidence: 99%

Murine glomerular leukotriene B4 synthesis. Manipulation by (n-6) fatty acid deprivation and cellular origin.

Lefkowith

Morrison²,

Schreiner³

1988

J. Clin. Invest.

View full text Add to dashboard Cite

Leukotriene (LT) B4 is an important pro-inflammatory autocoid. In order to investigate the potential role of this eicosanoid in renal inflammation, in this study we determined the capability of glomeruli to synthesize this mediator. Glomeruli were able to synthesize LTB4 when provided with exogenous substrate in a dose-dependent fashion in the presence of ionophore A23187. Ionophore, although by itself a weak agonist for LTB4 formation, was required for LTB4 production from exogenous arachidonate. The identity of LTB4 was confirmed by specific radioimmunoassay, high pressure liquid chromatography, and gas chromatography/mass spectrometry. The synthesis of LTB4 was inhibited by BW755C (a lipoxygenase/cyclooxygenase inhibitor) but not indomethacin. Essential fatty acid (EFA) deficiency, obtained by the deprivation of (n-6) fatty acids, is known to exert a protective effect in renal inflammatory states. This dietary manipulation markedly attenuated the ability of glomeruli to synthesize LTB4. In contrast, the synthesis of cyclooxygenase products from exogenous arachidonate was increased by EFA deficiency. Because EFA deficiency has been shown to deplete glomeruli of resident mesangial macrophages, it was hypothesized that this effect accounted for the diminished LTB4 synthesis. To test this hypothesis, glomeruli were depleted of macrophages using x-irradiation. Glomeruli from these animals exhibited a marked decrease in LTB4 synthesis. Glomerular synthesis of cyclooxygenase products was unaffected by irradiation. In sum, glomeruli have the capability to synthesize LTB4, and this capacity is correlated with the presence of glomerular macrophages. EFA deficiency attenuates the ability of glomeruli to synthesize LTB4 by depleting them of macrophages.

show abstract

“…LTB4 synthesis in the treated rats was 1.06 ng/mg glomerular protein, versus 2.96 ng/mg in untreated controls. (20,(27)(28)(29). On the other hand, the data on the role of the lipoxygenase metabolites in glomerular inflammation are few and the capacity of the glomeruli to synthesize 5-lipoxygenase products has not been established.…”

mentioning

confidence: 99%

Increased leukotriene B4 synthesis in immune injured rat glomeruli.

Rahman¹,

Nakazawa²,

Emancipator³

et al. 1988

J. Clin. Invest.

View full text Add to dashboard Cite

We examined glomerular synthesis of the 5-lipoxygenase metabolite, LTB4, in normal and immune-injured rat glomeruli.Glomeruli isolated from normal rats and from rats with nephrotoxic serum nephritis (NSN), passive Heymann nephritis (PHN) and cationic bovine gamma globulin (CBGG)-induced glomerulonephritis were incubated with the calcium ionophore A23187 (3 ,M). Lipids in the glomeruli and media were extracted with ethyl acetate, and were purified and fractionated by HPLC. Immunoreactive-LTB4 (i-LTB4) was determined by radioimmunoassay on HPLC fractions with a detection limit of 50 pg of i-LTB4. A large peak of i-LTB4 that comigrated with authentic LTB4 was found exclusively in glomeruli isolated from the CBGG-injected rats. Addition of the lipoxygenase inhibitor BW755C (50 ;&g/ml) to glomerular incubation resulted in > 90% inhibition of i-LTB4. Synthesis of i-LTB4 by glomeruli from normal, NSN and PHN rats was undetectable. Glomerular LTB4 synthesis by CBGG-injected rats was confirmed by radiometric HPLC and by gas chromatography mass-spectroscopy (GC-MS) analysis.In order to rule out synthesis of LTB4 by neutrophils entrapped in the glomeruli, a group of rats received 1,000 rad total body x irradiation, with shielding of the kidneys before induction of CBGG glomerulonephritis. Despite > 95% reduction in total leukocyte count, glomerular synthesis of LTB4 remained enhanced. Augmented glomerular synthesis of the proinflammatory lipid, LTB4, in the CBGG model of glomerular disease could have an important role in the development of glomerular injury and proteinuria. Introduction Several lipoxygenase products of arachidonic acid are synthesized in the kidney, especially in glomeruli. Murine and human glomeruli have lipoxygenase activity and metabolize arachidonic acid to 12-hydroxyeicosa tetraenoic acid (12-HETE) and 12-and 15-HETE, respectively (1, 2). Enhanced

show abstract

Increased glomerular thromboxane synthesis as a possible cause of proteinuria in experimental nephrosis.

Cited by 161 publications

References 20 publications

The EP4 Receptor for Prostaglandin E2 in Glomerular Disease

The EP4 Receptor for Prostaglandin E2 in Glomerular Disease

Murine glomerular leukotriene B4 synthesis. Manipulation by (n-6) fatty acid deprivation and cellular origin.

Increased leukotriene B4 synthesis in immune injured rat glomeruli.

Contact Info

Product

Resources

About