Presence of bioactive lysophosphatidic acid in renal effluent of rats with unilateral ureteral obstruction

Tsutsumi, Toshihiko; Adachi, Masayoshi; Nikawadori, Miki; Morishige, Jun‐ichi; Tokumura, Akira

doi:10.1016/j.lfs.2011.06.001

Cited by 26 publications

(12 citation statements)

References 36 publications

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“…In relation to uremia, it has been reported that patients with renal failure have 3‐fold elevated circulating LPA levels, compared to control subjects 24. More recently, this was confirmed in a rat model of unilateral urethral obstruction 25. Strikingly, in this study, elevated plasma LPA was accompanied by increased ATX activity in renal effluent, rather than in plasma.…”

Section: Discussionsupporting

confidence: 70%

Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions

et al. 2012

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Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro , RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values. Conclusion : Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR-dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis. (Hepatology 2012)

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Section: Discussionsupporting

confidence: 70%

Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions

et al. 2012

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“…LPA has been demonstrated to be produced in multiple tissues, 7,10,46 but the source(s) of LPA during the development of organ fibrosis remain to be established. In the UUO model, the concentrations of LPA in the effluent from the pelvis of the ligated kidney have been demonstrated to be significantly higher than those in the urinary bladder, suggesting that LPA is produced locally in the kidney during the course of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…In the UUO model, the concentrations of LPA in the effluent from the pelvis of the ligated kidney have been demonstrated to be significantly higher than those in the urinary bladder, suggesting that LPA is produced locally in the kidney during the course of renal fibrosis. 46 LPA can be produced by two major pathways. Of these, the pathway involving the enzyme autotaxin (ATX), which converts lysophospholipids such as lysophosphatidylcholine to LPA by its lysophospholipase D activity, is responsible for the most of LPA present in the circulation.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor

Sakai

Chun

Duffield

et al. 2017

Kidney International

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The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA1 expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA1 signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA1-deficient (LPA1−/−) or -sufficient (LPA1+/+) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I pro-collagen promoter (Col-GFP) to identify fibroblasts. Unilateral ureteral obstruction-induced increases in renal collagen were significantly, though not completely, attenuated in LPA1−/−Col-GFP mice, as were the accumulations of both fibroblasts and myofibroblasts. Connective tissue growth factor was detected mainly in tubular epithelial cells, and its levels were suppressed in LPA1 −/−Col-GFP mice. LPA-LPA1 signaling directly induced connective tissue growth factor expression in primary proximal tubular epithelial cells, through a myocardin-related transcription factor-serum response factor pathway. Proximal tubular epithelial cell derived connective tissue growth factor mediated renal fibroblast proliferation and myofibroblast differentiation. Administration of an inhibitor of myocardin-related transcription factor/serum response factor suppressed obstruction-induced renal fibrosis. Thus, targeting LPA-LPA1 signaling and/or myocardin-related transcription factor/serum response factor-induced transcription could be promising therapeutic strategies for renal fibrosis.

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“…12) Aliquots of lipid extracts (5 µL) were subjected to LC-MS/MS, and LPCs and LPAs were quantified by positive and negative ion modes, respectively, in multiple reaction monitoring as described.…”

Section: Lc-ms/ms Of Lpc and Lpa In Rat Plasmamentioning

confidence: 99%

Alterations of Plasma Levels of Lysophosphatidic Acid in Response to Fasting of Rats

Ino

Shimizu

Tanaka

et al. 2012

Biological & Pharmaceutical Bulletin

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The aim of this study was to investigate the effect of fasting on in vivo plasma levels of lysophosphatidic acid (LPA), a physiologically important lysophospholipid mediator. We assayed to measure activities of an LPA-producing enzyme (lysophospholipase D) and LPA-degrading enzyme activities (lysophspholipase A, lipid phosphate phosphatase) in rat plasma or blood, by measuring choline, fatty acid and inorganic phosphate, respectively. Both LPA and its precursor lysophosphatidylcholine (LPC) were quantified by liquid chromatography-tandem mass spectrometry. Fasting of rats for 24 h decreased plasma concentrations of oleoyl-, linoleoyl-, arachidonoyl-and docosahexaenoyl-LPAs, but not palmitoyl-and stearoyl-LPAs, possibly due to decreased levels of corresponding LPCs in the plasma and elevated lipid phosphate phosphatase activity for LPAs in the blood. Our results indicate that the in vivo circulating levels of LPAs in rats are affected by fasting.Key words autotaxin; lysophospholipase D; lysophosphatidylcholine; lysophospholipase A; lipid phosphate phosphatase; plasma Lysophosphatidic acid (LPA) is well-known as the first lipidic intermediate of the de novo synthetic pathway for glycero phospholipids. Increasing interest is currently being directed toward its extracellular actions through at least six specific G-protein coupled receptors.1) Both circulating and local levels of LPA are regulated tightly by LPA-producing enzymes, LPA-degrading enzymes and LPA-binding proteins.2,3) Both abnormal production and degradation of LPA are assumed to be relevant to pathophysiological conditions of human such as cancer metastasis, 4) atherosclerosis, 5) organ fibrosis 6) and pain. 7) Although LPA-producing enzymatic activity in human plasma and bovine fetal serum was demonstrated to be largely due to autotaxin (ATX), 8,9) physiological regulation of the circulating LPA level is not yet well understood. 3,10) In this study, we focused our inquiry on whether the stress of nutritional restriction affected the in vivo plasma level and molecular species composition of LPA using quantifying lysophosphatidylcholine (LPC) and LPA by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its mechanism by comparing LPA-producing and -degrading enzymatic activities during 12 and 24 h fasting. MATERIALS AND METHODSLysophospholipids Fatty acyl moieties of lysophospholipids are designated in terms of the combined number of carbon atoms : the combined number of double bonds. Palmitoyl (16 : 0)-, heptadecanoyl (17 : 0)-and linoleoyl (18 : 2)-LPCs were purchased from Avanti Polar Lipids (Alabaster, AL, U.S.A.). LPA having a heptadecanoyl group was prepared as described previously. 11)Animals Control male Wistar rats (9 wks old) were freely fed a standard chow (Japan SLC, Shizuoka, Japan) until experiments, whereas test rats of the same age were subjected to fasting for 12 h or 24 h. For blood collection, fasted and non-fasted rats were anesthetized with diethyl ether and blood was withdrawn from a catheter inserted into an abdominal a...

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Presence of bioactive lysophosphatidic acid in renal effluent of rats with unilateral ureteral obstruction

Cited by 26 publications

References 36 publications

Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions

Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions

Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor

Alterations of Plasma Levels of Lysophosphatidic Acid in Response to Fasting of Rats

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