Physiologic and pathophysiologic roles of lipid mediators in the kidney
2007; Elsevier BV; Volume: 71; Issue: 11 Linguagem: Inglês
10.1038/sj.ki.5002192
ISSN1523-1755
AutoresChuan‐Ming Hao, Matthew D. Breyer,
Tópico(s)Nitric Oxide and Endothelin Effects
ResumoSmall lipids such as eicosanoids exert diverse and complex functions. In addition to their role in regulating normal kidney function, these lipids also play important roles in the pathogenesis of kidney diseases. Cyclooxygenase (COX)-derived prostanoids play important role in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly (PGI2) and PGE2 play critical roles in maintaining blood pressure and renal function in volume contracted states. Renal medullary COX2-derived prostanoids appear to have antihypertensive effect in individuals challenged with a high salt diet. 5-Lipoxygenase (LO)-derived leukotrienes are involved in inflammatory glomerular injury. LO product 12-hydroxyeicosatetraenoic acid (12-HETE) is associated with pathogenesis of hypertension, and may mediate angiotensin II and TGFβ induced mesengial cell abnormality in diabetic nephropathy. P450 hydroxylase-derived 20-HETE is a potent vasoconstrictor and is involved in the pathogenesis of hypertension. P450 epoxygenase derived epoxyeicosatrienoic acids (EETs) have vasodilator and natriuretic effect. Blockade of EET formation is associated with salt-sensitive hypertension. Ceramide has also been demonstrated to be an important signaling molecule, which is involved in pathogenesis of acute kidney injury caused by ischemia/reperfusion, and toxic insults. Those pathways should provide fruitful targets for intervention in the pharmacologic treatment of renal disease. Small lipids such as eicosanoids exert diverse and complex functions. In addition to their role in regulating normal kidney function, these lipids also play important roles in the pathogenesis of kidney diseases. Cyclooxygenase (COX)-derived prostanoids play important role in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly (PGI2) and PGE2 play critical roles in maintaining blood pressure and renal function in volume contracted states. Renal medullary COX2-derived prostanoids appear to have antihypertensive effect in individuals challenged with a high salt diet. 5-Lipoxygenase (LO)-derived leukotrienes are involved in inflammatory glomerular injury. LO product 12-hydroxyeicosatetraenoic acid (12-HETE) is associated with pathogenesis of hypertension, and may mediate angiotensin II and TGFβ induced mesengial cell abnormality in diabetic nephropathy. P450 hydroxylase-derived 20-HETE is a potent vasoconstrictor and is involved in the pathogenesis of hypertension. P450 epoxygenase derived epoxyeicosatrienoic acids (EETs) have vasodilator and natriuretic effect. Blockade of EET formation is associated with salt-sensitive hypertension. Ceramide has also been demonstrated to be an important signaling molecule, which is involved in pathogenesis of acute kidney injury caused by ischemia/reperfusion, and toxic insults. Those pathways should provide fruitful targets for intervention in the pharmacologic treatment of renal disease. An extensive body of evidence demonstrates that small lipids participate as mediators in a variety of trans-membrane signaling cascades, mediating multiple cellular processes such as cell differentiation, replication, and apoptosis.1.Brash A.R. Arachidonic acid as a bioactive molecule.J Clin Invest. 2001; 107: 1339-1345Crossref PubMed Google Scholar, 2.Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (1940) Google Scholar, 3.Fitzpatrick F.A. Soberman R. Regulated formation of eicosanoids.J Clin Invest. 2001; 107: 1347-1351Crossref PubMed Google Scholar, 4.FitzGerald G.A. Loll P. COX in a crystal ball: current status and future promise of prostaglandin research.J Clin Invest. 2001; 107: 1335-1337Crossref PubMed Google Scholar These lipids include eicosanoids, fatty acids, glycerophospholipids, and ceramides.1.Brash A.R. Arachidonic acid as a bioactive molecule.J Clin Invest. 2001; 107: 1339-1345Crossref PubMed Google Scholar, 2.Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (1940) Google Scholar, 3.Fitzpatrick F.A. Soberman R. Regulated formation of eicosanoids.J Clin Invest. 2001; 107: 1347-1351Crossref PubMed Google Scholar, 4.FitzGerald G.A. Loll P. COX in a crystal ball: current status and future promise of prostaglandin research.J Clin Invest. 2001; 107: 1335-1337Crossref PubMed Google Scholar In addition to their roles in regulating physiologic function, these lipid mediators have also been demonstrated to play important roles in the pathophysiology of inflammation, asthma, cancer, diabetes, and hypertension,1.Brash A.R. Arachidonic acid as a bioactive molecule.J Clin Invest. 2001; 107: 1339-1345Crossref PubMed Google Scholar, 2.Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (1940) Google Scholar, 3.Fitzpatrick F.A. Soberman R. Regulated formation of eicosanoids.J Clin Invest. 2001; 107: 1347-1351Crossref PubMed Google Scholar, 4.FitzGerald G.A. Loll P. COX in a crystal ball: current status and future promise of prostaglandin research.J Clin Invest. 2001; 107: 1335-1337Crossref PubMed Google Scholar, 5.Capdevila J.H. Harris R.C. Falck J.R. Microsomal cytochrome P450 and eicosanoid metabolism.Cell Mol Life Sci. 2002; 59: 780-789Crossref PubMed Scopus (51) Google Scholar pointing to potential therapeutic targets at these lipid mediators or the enzyme responsible for their biosynthesis or the receptor mediating their actions. The present review will focus on the current understanding of the roles of arachidonic acid-derived lipid mediators in mediating normal physiologic function and pathologic events of the kidney. Eicosanoids are 20 carbon fatty acid derivatives (eicosa, Greek for 20), produced from arachidonic acid through three major enzymatic pathways: cyclooxygenase (COX), lipoxygenase (LO), and cytochrome P450 monooxygenase (CYP450).2.Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (1940) Google Scholar, 3.Fitzpatrick F.A. Soberman R. Regulated formation of eicosanoids.J Clin Invest. 2001; 107: 1347-1351Crossref PubMed Google Scholar, 5.Capdevila J.H. Harris R.C. Falck J.R. Microsomal cytochrome P450 and eicosanoid metabolism.Cell Mol Life Sci. 2002; 59: 780-789Crossref PubMed Scopus (51) Google Scholar, 6.Smith W.L. Prostanoid biosynthesis and mechanisms of action.Am J Physiol. 1992; 263: F181-F191PubMed Google Scholar, 7.Hla T. Bishop-Bailey D. Liu C.H. et al.Cyclooxygenase-1 and -2 isoenzymes.Int J Biochem Cell Biol. 1999; 31: 551-557Crossref PubMed Scopus (155) Google Scholar Eicosanoids include prostanoids derived from COX pathway, leukotrienes from LO pathway and hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) from P450 monooxygenase pathway.2.Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (1940) Google Scholar, 3.Fitzpatrick F.A. Soberman R. Regulated formation of eicosanoids.J Clin Invest. 2001; 107: 1347-1351Crossref PubMed Google Scholar, 5.Capdevila J.H. Harris R.C. Falck J.R. Microsomal cytochrome P450 and eicosanoid metabolism.Cell Mol Life Sci. 2002; 59: 780-789Crossref PubMed Scopus (51) Google Scholar, 6.Smith W.L. Prostanoid biosynthesis and mechanisms of action.Am J Physiol. 1992; 263: F181-F191PubMed Google Scholar, 7.Hla T. Bishop-Bailey D. Liu C.H. et al.Cyclooxygenase-1 and -2 isoenzymes.Int J Biochem Cell Biol. 1999; 31: 551-557Crossref PubMed Scopus (155) Google Scholar Arachidonic acid, a precursor of eicosanoids, exists primarily in esterified form as a glycerophospholipid in the cell membrane. Cellular levels of free arachidonic acid available for eicosanoid production is primarily controlled by phospholipase A2 (PLA2).8.Bonventre J.V. The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biology.J Am Soc Nephrol. 1999; 10: 404-412PubMed Google Scholar Thus far more than 20 PLA2s have been identified, which have been classified into four groups: secretory PLA2 (sPLA2), cytosolic PLA2 (cPLA2), calcium independent PLA2 (iPLA2), and PAF acetylhydrolases (PAF-AH).8.Bonventre J.V. The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biology.J Am Soc Nephrol. 1999; 10: 404-412PubMed Google Scholar,9.Kudo I. Murakami M. Phospholipase A2 enzymes.Prostaglandins Other Lipid Mediat. 2002; 68–69: 3-58Crossref PubMed Scopus (530) Google Scholar Five members of cPLA2 family have been identified: cPLA2α, β, δ, ε, ζ, and γ.10.Shimizu T. Ohto T. Kita Y. Cytosolic phospholipase A2: biochemical properties and physiological roles.IUBMB Life. 2006; 58: 328-333Crossref PubMed Scopus (48) Google Scholar Among them, cPLA2α (IVA PLA2) is best characterized and is suggested to be a key player for arachidonic acid release.8.Bonventre J.V. The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biology.J Am Soc Nephrol. 1999; 10: 404-412PubMed Google Scholar,9.Kudo I. Murakami M. Phospholipase A2 enzymes.Prostaglandins Other Lipid Mediat. 2002; 68–69: 3-58Crossref PubMed Scopus (530) Google Scholar cPLA2 can be phosphorylated by several protein kinases including mitogen-activated protein kinase, protein kinase C (PKC), and Ca2+-calmodulin-dependent kinase.11.Clark J.D. Lin L.L. Kriz R.W. et al.A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP.Cell. 1991; 65: 1043-1051Abstract Full Text PDF PubMed Scopus (1159) Google Scholar, 12.Clark J.D. Milona N. Knopf J.L. Purification of a 110-kilodalton cytosolic phospholipase A2 from the human monocytic cell line U937.Proc Natl Acad Sci USA. 1990; 87: 7708-7712Crossref PubMed Google Scholar, 13.Sharp J.D. White D.L. Chiou X.G. et al.Molecular cloning and expression of human Ca(2+)-sensitive cytosolic phospholipase A2.J Biol Chem. 1991; 266: 14850-14853Abstract Full Text PDF PubMed Google Scholar Several vasoactive substances, such as endothelin, angiotensin II (ANG II), and vasopressin, have been reported to activate cPLA2.14.Barnett R.L. Ruffini L. Hart D. et al.Mechanism of endothelin activation of phospholipase A2 in rat renal medullary interstitial cells.Am J Physiol. 1994; 266: F46-F56PubMed Google Scholar, 15.Resink T.J. Scott-Burden T. Buhler F.R. Activation of phospholipase A2 by endothelin in cultured vascular smooth muscle cells.Biochem Biophys Res Commun. 1989; 158: 279-286Crossref PubMed Scopus (95) Google Scholar, 16.Schramek H. Wang Y. Konieczkowski M. et al.Endothelin-1 stimulates cytosolic phospholipase A2 activity and gene expression in rat glomerular mesangial cells.Kidney Int. 1994; 46: 1644-1652Abstract Full Text PDF PubMed Google Scholar, 17.Takakuwa T. Endo S. Nakae H. et al.Relationship between plasma levels of type II phospholipase A2, PAF acetylhydrolase, endothelin-1, and thrombomodulin in patients with infected burns.Res Commun Mol Pathol Pharmacol. 1994; 86: 335-340PubMed Google Scholar, 18.Dulin N.O. Alexander L.D. Harwalkar S. et al.Phospholipase A2-mediated activation of mitogen-activated protein kinase by angiotensin II.Proc Natl Acad Sci USA. 1998; 95: 8098-8102Crossref PubMed Scopus (66) Google Scholar, 19.Lehman J.J. Brown K.A. Ramanadham S. et al.Arachidonic acid release from aortic smooth muscle cells induced by [Arg8]vasopressin is largely mediated by calcium-independent phospholipase A2.J Biol Chem. 1993; 268: 20713-20716Abstract Full Text PDF PubMed Google Scholar, 20.Liu Y. Taylor C.W. Stimulation of arachidonic acid release by vasopressin in A7r5 vascular smooth muscle cells mediated by Ca2+-stimulated phospholipase A2.FEBS Lett. 2006; 580: 4114-4120Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar These properties of cPLA2 are consistent with its critical role in regulating arachidonic acid release and eicosanoid biosynthesis.8.Bonventre J.V. The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biology.J Am Soc Nephrol. 1999; 10: 404-412PubMed Google Scholar,9.Kudo I. Murakami M. Phospholipase A2 enzymes.Prostaglandins Other Lipid Mediat. 2002; 68–69: 3-58Crossref PubMed Scopus (530) Google Scholar In the kidney, PLA2 activity can be induced by a variety of stimuli, including oxidative stress, complement C5b-9, hypoxia, and mechanical stretch.21.Goto S. Nakamura H. Morooka H. et al.Role of reactive oxygen in phospholipase A2 activation by ischemia/reperfusion of the rat kidney.J Anesth. 1999; 13: 90-93Crossref PubMed Scopus (17) Google Scholar, 22.Cybulsky A.V. Takano T. Papillon J. et al.The actin cytoskeleton facilitates complement-mediated activation of cytosolic phospholipase A2.Am J Physiol Renal Physiol. 2004; 286: F466-F476Crossref PubMed Google Scholar, 23.Petry C. Huwiler A. Eberhardt W. et al.Hypoxia increases group IIA phospholipase A(2) expression under inflammatory conditions in rat renal mesangial cells.J Am Soc Nephrol. 2005; 16: 2897-2905Crossref PubMed Scopus (11) Google Scholar, 24.Alexander L.D. Alagarsamy S. Douglas J.G. Cyclic stretch-induced cPLA2 mediates ERK 1/2 signaling in rabbit proximal tubule cells.Kidney Int. 2004; 65: 551-563Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar It has been documented that cPLA2 can potentiate H2O2 cytotoxicity in kidney epithelial cells and glomerular mesangial cells.25.Sapirstein A. Spech R.A. Witzgall R. et al.Cytosolic phospholipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen peroxide cytotoxicity in kidney epithelial cells.J Biol Chem. 1996; 271: 21505-21513Crossref PubMed Scopus (113) Google Scholar,26.Sheridan A.M. Force T. Yoon H.J. et al.PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production.Mol Cell Biol. 2001; 21: 4470-4481Crossref PubMed Scopus (42) Google Scholar cPLA2 and its products have been reported to participate in several pathogenic process, including diabetic nephropathy, anti-Thy1 glomerulonephritis, and ischemic kidney injury.8.Bonventre J.V. The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biology.J Am Soc Nephrol. 1999; 10: 404-412PubMed Google Scholar,10.Shimizu T. Ohto T. Kita Y. Cytosolic phospholipase A2: biochemical properties and physiological roles.IUBMB Life. 2006; 58: 328-333Crossref PubMed Scopus (48) Google Scholar Recently, considerable evidence suggests that secretary PLA2s, particularly secretory PLA2 IIα, secretory PLA2 V, and secretory PLA2 X, are involved in atherosclerotic lesions.27.Boyanovsky B.B. van der Westhuyzen D.R. Webb N.R. Group V secretory phospholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independent process that involves cellular proteoglycans.J Biol Chem. 2005; 280: 32746-32752Crossref PubMed Scopus (53) Google Scholar, 28.Fuentes L. Hernandez M. Fernandez-Aviles F.J. et al.Cooperation between secretory phospholipase A2 and TNF-receptor superfamily signaling: implications for the inflammatory response in atherogenesis.Circ Res. 2002; 91: 681-688Crossref PubMed Scopus (30) Google Scholar, 29.Murakami M. Kudo I. New phospholipase A(2) isozymes with a potential role in atherosclerosis.Curr Opin Lipidol. 2003; 14: 431-436Crossref PubMed Scopus (62) Google Scholar Their roles in the kidney remain to be defined. Prostanoids are formed by conversion of free arachidonic acid to a common intermediate, PGH2 by COX via two enzymatic processes (Figure 1). COX first converts arachidonic acid to PGG2 via its bis-oxygenase activity, and the unstable PGG2 is then converted to PGH2 by the peroxidase activity of COX.30.Herschman H.R. Prostaglandin synthase 2.Biochim Biophys Acta. 1996; 1299: 125-140Crossref PubMed Google Scholar PGH2 is subsequently metabolized to more stable biologically active prostanoids including PGE2, prostacyclin (PGI2), PGF2α, PGD2, and thromboxane A2 by distinct synthases. Each prostanoid acts on specific and distinct cell surface G-protein coupled receptor(s)31.Breyer M.D. Breyer R.M. Prostaglandin receptors: their role in regulating renal function.Curr Opin Nephrol Hypertens. 2000; 9: 23-29Crossref PubMed Scopus (68) Google Scholar,32.Narumiya S. FitzGerald G.A. Genetic and pharmacological analysis of prostanoid receptor function.J Clin Invest. 2001; 108: 25-30Crossref PubMed Scopus (371) Google Scholar or on nuclear receptors such as peroxisome proliferator activated receptor (PPAR)δ and PPARγ33.Hao C.M. Redha R. Morrow J. et al.Peroxisome proliferator-activated receptor delta activation promotes cell survival following hypertonic stress.J Biol Chem. 2002; 277: 21341-21345Crossref PubMed Scopus (77) Google Scholar, 34.Lim H. Dey S.K. PPAR delta functions as a prostacyclin receptor in blastocyst implantation.Trends Endocrinol Metab. 2000; 11: 137-142Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 35.Bernardo A. Levi G. Minghetti L. Role of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its natural ligand 15-deoxy-Delta12, 14-prostaglandin J2 in the regulation of microglial functions.Eur J Neurosci. 2000; 12: 2215-2223Crossref PubMed Scopus (170) Google Scholar, 36.Ward J.E. Gould H. Harris T. et al.PPAR gamma ligands, 15-deoxy-delta12, 14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms.Br J Pharmacol. 2004; 141: 517-525Crossref PubMed Scopus (49) Google Scholar(Figure 1). Prostanoids are rapidly metabolically degraded, limiting their effect to the immediate vicinity of their synthetic site, accounting for their autocrine or paracrine function. The biologic effects of COX-derived prostanoids are diverse and complex, depending on which prostanoid is produced and which receptor is available.31.Breyer M.D. Breyer R.M. Prostaglandin receptors: their role in regulating renal function.Curr Opin Nephrol Hypertens. 2000; 9: 23-29Crossref PubMed Scopus (68) Google Scholar,32.Narumiya S. FitzGerald G.A. Genetic and pharmacological analysis of prostanoid receptor function.J Clin Invest. 2001; 108: 25-30Crossref PubMed Scopus (371) Google Scholar Thus the effects of prostanoids on kidney function will rely on distinct enzymatic machinery that couples phospholipase and COX to specific prostanoid synthase in specific cells, yielding a specific prostanoid, which acts, through autocrine or paracrine, on a specific G-protein coupled receptor, exerting its distinct effect.31.Breyer M.D. Breyer R.M. Prostaglandin receptors: their role in regulating renal function.Curr Opin Nephrol Hypertens. 2000; 9: 23-29Crossref PubMed Scopus (68) Google Scholar Two isoforms of COX have been identified, designated COX1 and COX2.37.Simmons D.L. Levy D.B. Yannoni Y. et al.Identification of a phorbol ester-repressible v-src-inducible gene.Proc Natl Acad Sci USA. 1989; 86: 1178-1182Crossref PubMed Google Scholar, 38.Guan Y. Chang M. Cho W. et al.Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells.Am J Physiol. 1997; 273: F18-F26PubMed Google Scholar, 39.Hla T. Neilson K. Human cyclooxygenase-2 cDNA.Proc Natl Acad Sci USA. 1992; 89: 7384-7388Crossref PubMed Google Scholar, 40.Kujubu D.A. Fletcher B.S. Varnum B.C. et al.TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.J Biol Chem. 1991; 266: 12866-12872Abstract Full Text PDF PubMed Google Scholar COX1 appears to serve a constitutive house-keeping role, responsible for maintaining basic physiological function such as cytoprotection of the gastric mucosa, and control of platelet aggregation.6.Smith W.L. Prostanoid biosynthesis and mechanisms of action.Am J Physiol. 1992; 263: F181-F191PubMed Google Scholar, 30.Herschman H.R. Prostaglandin synthase 2.Biochim Biophys Acta. 1996; 1299: 125-140Crossref PubMed Google Scholar, 41.Smith W.L. Langenbach R. Why there are two cyclooxygenase isozymes.J Clin Invest. 2001; 107: 1491-1495Crossref PubMed Google Scholar Conversely, COX2 is induced by inflammatory mediators and mitogens, and is thought to play a key role in pathophysiologic processes including angiogenesis, inflammation, and tumorigenesis.6.Smith W.L. Prostanoid biosynthesis and mechanisms of action.Am J Physiol. 1992; 263: F181-F191PubMed Google Scholar, 7.Hla T. Bishop-Bailey D. Liu C.H. et al.Cyclooxygenase-1 and -2 isoenzymes.Int J Biochem Cell Biol. 1999; 31: 551-557Crossref PubMed Scopus (155) Google Scholar, 30.Herschman H.R. Prostaglandin synthase 2.Biochim Biophys Acta. 1996; 1299: 125-140Crossref PubMed Google Scholar, 41.Smith W.L. Langenbach R. Why there are two cyclooxygenase isozymes.J Clin Invest. 2001; 107: 1491-1495Crossref PubMed Google Scholar However, recent studies indicate that COX2 also serves 'house-keeping' functions. Gene targeting experiments demonstrated a critical role of COX2 in kidney development, in ovulation and parturition.42.Dinchuk J.E. Car B.D. Focht R.J. et al.Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II.Nature. 1995; 378: 406-409Crossref PubMed Google Scholar, 43.Morham S.G. Langenbach R. Loftin C.D. et al.Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse.Cell. 1995; 83: 473-482Abstract Full Text PDF PubMed Scopus (907) Google Scholar, 44.Komhoff M. Wang J.L. Cheng H.F. et al.Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development.Kidney Int. 2000; 57: 414-422Abstract Full Text Full Text PDF PubMed Google Scholar, 45.Lim H. Paria B.C. Das S.K. et al.Multiple female reproductive failures in cyclooxygenase 2-deficient mice.Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (997) Google Scholar Clinical studies as well as animal studies also demonstrated important role of COX2 in maintaining cardiovascular homeostasis.46.Bresalier R.S. Sandler R.S. Quan H. et al.Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.N Engl J Med. 2005; 352: 1092-1102Crossref PubMed Scopus (1799) Google Scholar, 47.Zewde T. Mattson D.L. Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension.Hypertension. 2004; 44: 424-428Crossref PubMed Scopus (65) Google Scholar, 48.Zhang J. Ding E.L. Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials.JAMA. 2006; 296: 1619-1632Crossref PubMed Scopus (185) Google Scholar In the kidney, COX1 is highly expressed in the collecting duct, and low level of COX1 can also be detected in interstitial cells.49.Harris R.C. McKanna J.A. Akai Y. et al.Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.J Clin Invest. 1994; 94: 2504-2510Crossref PubMed Google Scholar, 50.Yang T. Singh I. Pham H. et al.Regulation of cyclooxygenase expression in the kidney by dietary salt intake.Am J Physiol. 1998; 274: F481-F489PubMed Google Scholar, 51.Castrop H. Schweda F. Schumacher K. et al.Role of renocortical cyclooxygenase-2 for renal vascular resistance and macula densa control of renin secretion.J Am Soc Nephrol. 2001; 12: 867-874PubMed Google Scholar In contrast, COX2 is predominately expressed in renal medullary interstitial cells and in cortical thick ascending limb and cells associated with macula densa under normal conditions.38.Guan Y. Chang M. Cho W. et al.Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells.Am J Physiol. 1997; 273: F18-F26PubMed Google Scholar, 49.Harris R.C. McKanna J.A. Akai Y. et al.Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.J Clin Invest. 1994; 94: 2504-2510Crossref PubMed Google Scholar, 52.Hao C.M. Komhoff M. Guan Y. et al.Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival.Am J Physiol. 1999; 277: F352-F359PubMed Google Scholar PGH2, the product of COX-mediated arachidonate metabolism, is further metabolized by prostanoid synthase. Prostanoid synthases include PGE2 synthase (PGES), prostacyclin synthase (PGIS), PGD synthase (PGDS), PGF synthase (PGFS), and thromboxane synthase, responsible for PGE2, PGI2, PGD2, PGF2α, and thromboxane A2 biosynthesis, respectively.41.Smith W.L. Langenbach R. Why there are two cyclooxygenase isozymes.J Clin Invest. 2001; 107: 1491-1495Crossref PubMed Google Scholar,53.FitzGerald G.A. COX-2 and beyond: approaches to prostaglandin inhibition in human disease.Nat Rev Drug Discov. 2003; 2: 879-890Crossref PubMed Google Scholar At least three PGE synthases have been identified: microsomal PGE synthase 1 (mPGES1), microsomal PGE synthase 2 (mPGES), and cytosolic PGE synthase (cPGES1).54.Jakobsson P.J. Thoren S. Morgenstern R. et al.Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.Proc Natl Acad Sci USA. 1999; 96: 7220-7225Crossref PubMed Scopus (707) Google Scholar, 55.Tanioka T. Nakatani Y. Semmyo N. et al.Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis.J Biol Chem. 2000; 275: 32775-32782Crossref PubMed Scopus (598) Google Scholar, 56.Tanikawa N. Ohmiya Y. Ohkubo H. et al.Identification and characterization of a novel type of membrane-associated prostaglandin E synthase.Biochem Biophys Res Commun. 2002; 291: 884-889Crossref PubMed Scopus (227) Google Scholar mPGES1 displays a high catalytic activity relative to other PGESs.54.Jakobsson P.J. Thoren S. Morgenstern R. et al.Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.Proc Natl Acad Sci USA. 1999; 96: 7220-7225Crossref PubMed Scopus (707) Google Scholar,57.Lazarus M. Kubata B.K. Eguchi N. et al.Biochemical characterization of mouse microsomal prostaglandin E synthase-1 and its colocalization with cyclooxygenase-2 in peritoneal macrophages.Arch Biochem Biophys. 2002; 397: 336-341Crossref PubMed Scopus (54) Google Scholar The expression of mPGES1 is induced by cytokines and inflammatory stimuli.54.Jakobsson P.J. Thoren S. Morgenstern R. et al.Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.Proc Natl Acad Sci USA. 1999; 96: 7220-7225Crossref PubMed Scopus (707) Google Scholar In contrast, the expression of cPGES and mPGES2 is not inducible.56.Tanikawa N. Ohmiya Y. Ohkubo H. et al.Identification and characterization of a novel type of membrane-associated prostaglandin E synthase.Biochem Biophys Res Commun. 2002; 291: 884-889Crossref PubMed Scopus (227) Google Scholar,58.Murakami M. Nakatani Y. Tanioka T. et al.Prostaglandin E synthase.Prostaglandins Other Lipid Mediat. 2002; 68–69: 383-399Crossref PubMed Scopus (183) Google Scholar PGD2 is synthesized from PGH2 catalyzed by PGD synthase (PGDS).59.Urade Y. Eguchi N. Lipocalin-type and hematopoietic prostaglandin D synthases as a novel example of functional convergence.Prostaglandins Other Lipid Mediat. 2002; 68–69: 375-382Crossref PubMed Scopus (120) Google Scholar Two distinct types of PGDS have been identified: the lipocalin-type PGDS (L-PGDS) and the hematopoietic PGDS (H-PGDS).59.Urade Y. Eguchi N. Lipocalin-type and hematopoietic prostaglandin D synthases as a novel example of functional convergence.Prostaglandins Other Lipid Mediat. 2002; 68–69: 375-382Crossref PubMed Scopus (120) Google Scholar,60.Urade Y. Hayaishi O. Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase.Biochim Biophys Acta. 2000; 1482: 259-271Crossref PubMed Scopus (225) Google Scholar PGF2α can be synthesized from PGH2 by 9,11 endoperoxide reductase.61.Watanabe K. Prostaglandin F synthase.Prostaglandins Other Lipid Mediat. 2002; 68–69: 401-407Crossref PubMed Scopus (83) Google Scholar PGF2α can also be synthesized from PGE2 by PGE 9-ketoreductase.62.Lee S.C. Levine L. Purification and regulatory properties of chicken heart prostaglandin E 9-ketoreductase.J Biol Chem. 1975; 250: 4549-4555PubMed Google Scholar,63.Westbrook C. Jarabak J. Purification and partial characterization of an NADH-linked delta13–15-ketoprostaglandin reductase from human placenta.Biochem Biophys Res Commun. 1975; 66: 541-546Crossref PubMed Google Scholar The distribution of prostanoid synthases within the kidney is less well characterized. In the kidney, mPGES1 is expressed in collecting duct and medullary interstitial cells.64.Schneider A. Zhang Y. Zhang M. et al.Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney.Kidney Int. 2004; 65: 1205-1213Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,65.Vitzthum H. Abt I. Einhellig S. et al.Gene expression of prostanoid forming enzymes along the rat nephron.Kidney Int. 2002; 62: 1570-1581Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Although mPGES1 has been reported to be functionally coupled to COX2,58.Murakami M. Nakatani Y. Tanioka T. et al.Prostaglandin E synthase.Prostaglandins Other Lipid Mediat. 2002; 68–69: 383-399Crossref PubMed Scopus (183) Google Scholar in renal collecting duct mPGES1 appears to be mainly coupled to COX1.64.Schneider A. Zhang Y. Zhang M. et al.Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and
Referência(s)