Mechanism of the antiproteinuric effect of indomethacin in nephrotic humans

Golbetz, Helen; Black, Virginia H.; Shemesh, Ovadia; Myers, Bryan D.

doi:10.1152/ajprenal.1989.256.1.f44

Cited by 28 publications

(21 citation statements)

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“…PAH clearance values were used as a marker of glomerular plasma flow. As the extraction of PAH is incomplete in advanced renal failure, an extraction rate of 0.7 was assumed in patients with a GFR < 40 ml/min (11).…”

Section: Methodsmentioning

confidence: 99%

Glomerular permselectivity in proteinuric patients after kidney transplantation.

Oberbauer

Haas²,

Regele³

et al. 1995

J. Clin. Invest.

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To characterize the defect in glomerular permselectivity responsible for proteinuria after renal transplantation, we studied 10 patients with moderate proteinuria (median 0.37 g/d, range 0.20-0.79), 16 patients with the nephrotic syndrome (6.73 g/d, 3.9-14.6), 8 living related donor transplant recipients without any history of rejection (median proteinuria 0.26 g/d, 0.06-0.58), and 12 healthy volunteers. The fractional clearance of neutral dextrans > 54 A was significantly higher in nephrotic patients, demonstrating a defect in glomerular size selectivity. Using a log-normal model of glomerular pore size distribution, r*(5%) and r*(l%), indices for the presence of large pores, were increased in the nephrotic patients. The fractional clearance of negatively charged dextran sulfate was significantly higher in all patient groups, indicating a loss of glomerular charge selectivity. Biopsy findings showed more prominent glomerular lesions in the nephrotic group compared with the moderately proteinuric group. We conclude that mild proteinuria late after renal transplantation is associated with a defect in glomerular charge selectivity. The development of nephrotic range proteinuria is associated also with a defect of glomerular size selectivity, which correlates with prominent glomerular pathology. (J. Clin. Invest. 1995. 96:22-29.)

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Section: Methodsmentioning

confidence: 99%

Glomerular permselectivity in proteinuric patients after kidney transplantation.

Oberbauer

Haas²,

Regele³

et al. 1995

J. Clin. Invest.

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“…cPLA 2 is an important mediator of C5b-9-dependent GEC injury. First, arachidonic acid (AA) released by cPLA 2 is metabolized in GEC via cyclooxygenases-1 and -2 to prostaglandin E 2 and thromboxane A 2 (20), and inhibition of prostanoid production reduces proteinuria in PHN (21)(22)(23)(24)(25) and in human membranous nephropathy (26). Second, cPLA 2 may mediate GEC injury more directly (16).…”

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confidence: 99%

Complement C5b-9 Membrane Attack Complex Increases Expression of Endoplasmic Reticulum Stress Proteins in Glomerular Epithelial Cells

Cybulsky¹,

Takano²,

Papillon³

et al. 2002

Journal of Biological Chemistry

110

148

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In the passive Heymann nephritis (PHN) model of membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury, proteinuria, and activation of cytosolic phospholipase A 2 (cPLA 2 ). This study addresses the role of endoplasmic reticulum (ER) stress proteins (bip, grp94) in GEC injury. GEC that overexpress cPLA 2 (produced by transfection) and "neo" GEC (which expresses cPLA 2 at a lower level) were incubated with complement (40 min), and leakage of constitutively expressed bip and grp94 from ER into cytosol was measured to monitor ER injury. Greater leakage of bip and grp94 occurred in complement-treated GEC that overexpress cPLA 2 , as compared with neo, implying that cPLA 2 activation perturbed ER membrane integrity. After chronic incubation (4 -24 h), C5b-9 increased bip and grp94 mRNAs and proteins, and the increases were dependent on cPLA 2 . Expression of bip-antisense mRNA reduced stimulated bip protein expression and enhanced complement-dependent GEC injury. Glomerular bip and grp94 proteins were up-regulated in proteinuric rats with PHN, as compared with normal control. Pretreatment of rats with tunicamycin or adriamycin, which increase ER stress protein expression, reduced proteinuria in PHN. Thus, C5b-9 injures the ER and enhances ER stress protein expression, in part, via activation of cPLA 2 . ER stress protein induction is a novel mechanism of protection from complement attack.

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“…Evidence for this is derived from studies using nonsteroidal anti-inflammatory drugs (NSAIDs), which block the production of prostaglandins. Interestingly, proteinuria can be reduced by pharmacological treatments with NSAIDs both in experimental models of glomerular injury and in clinical practice (13,23,35,(37)(38)(39). The mechanism of action of NSAIDs in this context is currently unknown.…”

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confidence: 99%

PGE₂ reduces arachidonic acid release in murine podocytes: evidence for an autocrine feedback loop

Lemieux

Rahal

Kennedy

2003

American Journal of Physiology-Cell Physiology

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Lemieux, Lyne I., Sherine S. Rahal, and Chris R. J. Kennedy. PGE2 reduces arachidonic acid release in murine podocytes: evidence for an autocrine feedback loop. Am J Physiol Cell Physiol 284: C302-C309, 2003. First published September 25, 2002 10.1152/ajpcell.00024.2002 production is associated with the progression of diseases such as membranous nephropathy, nephrotic syndrome, and anti-Thy1 nephritis. We investigated the signaling pathways that regulate the synthesis and actions of PGE2 in glomerular podocytes. To study its actions, we assessed the ability of PGE2 to regulate the production of its own precursor, arachidonic acid (AA), in a mouse podocyte cell line. PGE2 dose-dependently reduced phorbol ester (PMA)-mediated AA release. Inhibition of PMA-stimulated AA release by PGE2 was found to be cAMP/ PKA-dependent, because PGE2 significantly increased levels of this second messenger, whereas the inhibitory actions of PGE2 were reversed by PKA inhibition and reproduced by the cAMP-elevating agents forskolin and IBMX. PGE2 synthesis in this podocyte cell line increased fourfold at 60 min in response to PMA, coinciding with upregulation of cyclooxygenase (COX)-2 but not COX-1 levels. However, PGE2 synthesis was significantly reduced by COX-1-selective inhibition, yet to a lesser extent by COX-2-selective inhibition. Our findings suggest that PMA-stimulated PGE2 synthesis in mouse podocytes requires both basal COX-1 activity and induced COX-2 expression, and that PGE2 reduces PMAstimulated AA release in a cAMP/PKA-dependent manner. Such an autocrine regulatory loop might have important consequences for podocyte and glomerular function in the context of renal diseases involving PGE2 synthesis. adenosine 3Ј,5Ј-cyclic monophosphate; cyclooxygenase; E-prostanoid receptors PROSTAGLANDIN E 2 (PGE 2 ) is synthesized by the metabolism of phospholipase A 2 (PLA 2 )-derived arachidonic acid (AA) to prostaglandin G/H 2 via cyclooxygenase (COX) isoforms (COX-1 or COX-2), followed by the activity of prostaglandin E synthase (17). Thus, as in many other cell types, phospholipid-derived AA liberated in glomerular podocytes could serve as a substrate for PGE 2 synthesis depending on the available complement of COX isoforms. Interestingly, increased podocyte expression of COX-2 has been documented in both a diabetic rat model (20) as well as in a rat subtotal renal ablation model (41). This increased COX-2 expression might therefore translate into elevated PGE 2 levels acting on neighboring cells or the podocytes themselves. In such a scenario, COX-2-derived PGE 2 might therefore function as an autacoid in podocytes, interacting with one or more of its cell surface receptors.PGE 2 can interact with at least four G proteincoupled E-prostanoid (EP) receptor subtypes that have been cloned and characterized from a variety of species, including human, rabbit, rat, and mouse (1,2,5,12,16,28,32,42,44), and are designated EP 1 , EP 2 , EP 3 , and EP 4 . Several studies have confirmed the presence of both EP 1 and EP 4 receptor subtype...

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Mechanism of the antiproteinuric effect of indomethacin in nephrotic humans

Cited by 28 publications

References 0 publications

Glomerular permselectivity in proteinuric patients after kidney transplantation.

Glomerular permselectivity in proteinuric patients after kidney transplantation.

Complement C5b-9 Membrane Attack Complex Increases Expression of Endoplasmic Reticulum Stress Proteins in Glomerular Epithelial Cells

PGE₂ reduces arachidonic acid release in murine podocytes: evidence for an autocrine feedback loop

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