Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis.

Katoh, Tetsuo; Lianos, Elias A.; Fukunaga, Masao; Takahashi, Kihito; Badr, Kamal F.

doi:10.1172/jci116356

Cited by 35 publications

(42 citation statements)

References 38 publications

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“…The mechanical effects of these sub-GEC deposits such as retraction of GEC and reduced density of anionic sites in the lamina rara externa may be critical to the development of proteinuria (50). A number of other local mediators have been postulated to damage GBM and GEC, such as reactive oxygen species (52) and PGs (53). Increased expression of the transmembrane form of heparin-binding epidermal growth factor in the GBM has also been associated with the development of proteinuria in PHN and is postulated to contribute to proteinuria through abortive GEC mitogenesis (20).…”

Section: Pvg/c6mentioning

confidence: 99%

Induction of Passive Heymann Nephritis in Complement Component 6-Deficient PVG Rats

Spicer

Tran

Killingsworth

et al. 2007

The Journal of Immunology

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Passive Heymann nephritis (PHN), a model of human membranous nephritis, is induced in susceptible rat strains by injection of heterologous antisera to rat renal tubular Ag extract. PHN is currently considered the archetypal complement-dependent form of nephritis, with the proteinuria resulting from sublytic glomerular epithelial cell injury induced by the complement membrane attack complex (MAC) of C5b-9. This study examined whether C6 and MAC are essential to the development of proteinuria in PHN by comparing the effect of injection of anti-Fx1A antisera into PVG rats deficient in C6 (PVG/C6−) and normal PVG rats (PVG/c). PVG/c and PVG/C6− rats developed similar levels of proteinuria at 3, 7, 14, and 28 days following injection of antisera. Isolated whole glomeruli showed similar deposition of rat Ig and C3 staining in PVG/c and PVG/C6− rats. C9 deposition was abundant in PVG/c but was not detected in PVG/C6− glomeruli, indicating C5b-9/MAC had not formed in PVG/C6− rats. There was also no difference in the glomerular cellular infiltrate of T cells and macrophages nor the size of glomerular basement membrane deposits measured on electron micrographs. To examine whether T cells effect injury, rats were depleted of CD8+ T cells which did not affect proteinuria in the early heterologous phase but prevented the increase in proteinuria associated with the later autologous phase. These studies showed proteinuria in PHN occurs without MAC and that other mechanisms, such as immune complex size, early complement components, CD4+ and CD8+ T cells, disrupt glomerular integrity and lead to proteinuria.

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Section: Pvg/c6mentioning

confidence: 99%

Induction of Passive Heymann Nephritis in Complement Component 6-Deficient PVG Rats

Spicer

Tran

Killingsworth

et al. 2007

The Journal of Immunology

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“…The LTA 4 -GSH conjugate (LTC 4 ) 1 and its cleavage products, LTD 4 and LTE 4 , are powerful mediators of bronchoconstriction, vasoconstriction, mucus formation, and edema. As a result, they are important mediators of asthma, coronary artery spasm, and nephropathies (7)(8)(9)(10)(11)(12)(13)(14)(15). Prostaglandins play diverse biological roles and are involved in the development of the inflammatory response, inhibition of platelet aggregation, and regulation of immune responses (6).…”

mentioning

confidence: 99%

γ-Glutamyl Leukotrienase, a γ-Glutamyl Transpeptidase Gene Family Member, Is Expressed Primarily in Spleen

Carter

Shi²,

Barrios³

et al. 1998

Journal of Biological Chemistry

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We have recently identified a mouse enzyme termed ␥-glutamyl leukotrienase (GGL) that converts leukotriene C 4 (LTC 4 ) to leukotriene D 4 (LTD 4 ). It also cleaves some other glutathione (GSH) conjugates, but not GSH itself (Carter, B. Z., Wiseman, A. L., Orkiszewski, R., Ballard, K. D., Ou, C.-N., and Lieberman, M. W. (1997) J. Biol. Chem. 272, 12305-12310). We have now cloned a fulllength mouse cDNA coding for GGL activity and the corresponding gene. GGL and ␥-glutamyl transpeptidase constitute a small gene family. The two cDNAs share a 57% nucleotide identity and 41% predicted amino acid sequence identity. Their corresponding genes have a similar intron-exon organization and are located 3 kilobases apart. A search of Genbank and reverse transcription-polymerase chain reaction analysis failed to identify additional family members. Mapping of the GGL transcription start site revealed that the GGL promoter is TATA-less but contains an initiator, a control element for transcription initiation. Northern blots for GGL expression were negative. As judged by ribonuclease protection, in situ hybridization, and measurement of enzyme activity, spleen had the highest level of GGL expression. GGL is also expressed in thymic lymphocytes, bronchiolar epithelial cells, pulmonary interstitial cells, renal proximal convoluted tubular cells, and crypt cells of the small intestine as well as in cerebral, cerebellar, and brain stem neurons but not in glial cells. GGL is widely distributed in mice, suggesting an important role for this enzyme.Glutathione conjugates play a central role in normal physiology and in responses to injury (1-6). Among the more important GSH derivatives are conjugates of eicosanoids, xenobiotics, and carcinogens. At least three types of eicosanoid-GSH conjugates have been identified, including derivatives of leukotriene A 4 , prostaglandins, and hepoxilins. The LTA 4 -GSH conjugate (LTC 4 ) 1 and its cleavage products, LTD 4 and LTE 4 , are powerful mediators of bronchoconstriction, vasoconstriction, mucus formation, and edema. As a result, they are important mediators of asthma, coronary artery spasm, and nephropathies (7-15). Prostaglandins play diverse biological roles and are involved in the development of the inflammatory response, inhibition of platelet aggregation, and regulation of immune responses (6). Prostaglandins are inactivated and cleared by conjugation to GSH (3, 6). Hepoxilin A 3 forms a GSH conjugate, hepoxilin A 3 -C, that is known to be a potent regulator of hippocampal neurons (4). In addition, several neurotransmitters, including serotonin and dopamine, form GSH conjugates, suggesting an additional role for this pathway in the central nervous system (16,17). GSH conjugation along with glucuronide formation is the major pathway by which toxins, drugs, and carcinogens such as CH 3 Hg, acetaminophen, and aflatoxin are detoxified and excreted (5, 18 -21).Until recently, it was thought that the sequential cleavage of GSH conjugates and their derivative cysteinyl-glycine conjugates were c...

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“…In particular, LTD 4 is one of the major components of the slow-reacting substances of anaphylaxis which are composed of LTB 4 , LTC 4 , LTD 4 , and LTE 4 . LTD 4 possesses a large number of functional effects, such as the increase of vascular permeability, the contraction of smooth muscles, and mucus secretion [3]. LTD 4 also mediates glomerular hemodynamic abnormalities in the kidney [4].…”

mentioning

confidence: 99%

“…LTD 4 possesses a large number of functional effects, such as the increase of vascular permeability, the contraction of smooth muscles, and mucus secretion [3]. LTD 4 also mediates glomerular hemodynamic abnormalities in the kidney [4].…”

mentioning

confidence: 99%

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Leukotriene D<sub>4</sub> Inhibits Na<sup>+</sup> Uptake through cAMP and PLC Pathways in Primary Cultured Renal Proximal Tubular Cells

Han

Park²,

Lee³

et al. 1999

Kidney Blood Press Res

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Leukotriene D4 (LTD4) is one of the slow-reacting substances of anaphylaxis and is reported to have a diverse response including the mediation of glomerular nephritis. However, little is known about the functions of LTD4 and its mechanisms of action in primary cultured rabbit renal proximal tubular cells (PTCs). The purpose of this study is to investigate the effect of LTD4 on Na+ uptake and its related signal transduction pathways in PTCs. LTD4 (>10(-9) M) significantly inhibited the Na+ uptake after 15 min (in nmol/mg protein: controls 431.7+/-11.4 vs. LTD4 (10(-9) M) 355.0+/-23.6; p<0. 05); and its effect was blocked by MK-571 (10(-6) M), a leukotriene receptor antagonist, in PTCs. Preincubation with cilastatin, a renal dipeptidase inhibitor, and polyclonal antibody against renal dipeptidase potentiated the inhibitory effect of LTD4 on Na+ uptake. SQ 22536 (10(-6) M), an adenylate cyclase inhibitor, and the myristoylated protein kinase A inhibitor amide 14-22 (PKI; 10(-5) M) blocked the effect of LTD4 on Na+ uptake (in nmol/mg protein: LTD4 349.9+/-18.5 vs. SQ 22536+LTD4 476.5+/-22.0 and PKI+LTD4 440.3+/-19. 3; p<0.05), and LTD4 induced an increase in cyclic adenosine monophosphate (cAMP), suggesting the involvement of cAMP in the inhibition of Na+ uptake. In addition, U 73122 (10(-6) M) and neomycin (10(-4) M), phospholipase C (PLC) inhibitors, W-7 (10(-4) M), a calmodulin antagonist, and bisindolylmaleimide I, a protein kinase C (PKC) inhibitor, blocked the LTD4-induced inhibition of Na+ uptake, strongly suggesting involvement of the PLC-PKC signal pathways in the effect of LTD4. LTD4 significantly increased [Ca2]i by 49+/-7% as compared with baseline. TMB-8 (10(-5) M) and BAPTA/AM (10(-5) M), intracellular calcium mobilization blockers, completely blocked the LTD4-induced inhibition of Na+ uptake (in nmol/mg protein: LTD4 347.6+/-19.0 vs. TMB-8+LTD4 436.4+/-22.3 and BAPTA/AM+LTD4 419.9+/-14.3; p<0.05); however, EGTA (1 mM), a calcium chelator, partially blocked the LTD4-induced inhibition of Na+ uptake. In conclusion, LTD4-induced inhibition of Na+ uptake may be involved in both cAMP and PLC-PKC signal pathways in PTCs. In addition, Ca2+, which comes from the intracellular Ca2+ mobilization, is primarily responsible for the LTD4-induced inhibition of Na+ uptake.

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Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis.

Cited by 35 publications

References 38 publications

Induction of Passive Heymann Nephritis in Complement Component 6-Deficient PVG Rats

Induction of Passive Heymann Nephritis in Complement Component 6-Deficient PVG Rats

γ-Glutamyl Leukotrienase, a γ-Glutamyl Transpeptidase Gene Family Member, Is Expressed Primarily in Spleen

Leukotriene D<sub>4</sub> Inhibits Na<sup>+</sup> Uptake through cAMP and PLC Pathways in Primary Cultured Renal Proximal Tubular Cells

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