Dokument

Zusammenfassung:
Leitsymptome des Hyperprostaglandinsyndroms sind neben einer erhöhten renalen Salz- und Wasserausscheidung eine verstärkte Reninproduktion, eine Hyperkalzurie und eine Hypertrophie des juxtaglomerulären Apparates. Bereits pränatal kommt es zur Ausbildung einer fetalen Polyurie, welche zur Ausbildung eines Polyhydramnions führen kann. Hierin ist die extrem gesteigerte Frühgeburtlichkeitsrate zwischen der 28. und 34. SSW begründet. Für die klinischen Symptome Durst, Fieber und Wachstumsbeeinträchtigungen wird v. a. eine massiv erhöhte renale Ausscheidung von PGE2 verantwortlich gemacht. In der vorliegenden Arbeit wurde anhand von primär kultivierten Schweinenierenzellen des dicken aufsteigenden Teils der Henle-Schleife, die Regulation der Prostaglandinsynthese näher untersucht und der Einfluss von Elektrolyten überprüft. Nach Stimulation mit hypotoner Lösung wurde eine Zunahme der PGE2-Synthese, der Expression der mPGES-1 mRNA und der COX-1 und COX-2 mRNA sowie eine Zunahme des Proteins der COX-2 beobachtet. Welche Art der Elektrolytveränderung hierfür ausschlaggebend ist, v. a. ob der Chloridentzug der maßgebliche Faktor ist, muss in Experimenten weiter geklärt werden. Unter isoosmolaren Bedingungen zeigte sich ebenfalls eine Expression der PGES-1, allerdings weniger deutlich als nach Stimulation mit hypoosmolarem Medium. Somit lässt sich durchaus eine Beteiligung der PGES-1 an der PGE2-Bildung bei Veränderung des zellulären Salzhaushaltes vermuten. Meine Ergebnisse geben darüber hinaus Anlass anzunehmen, dass die gesteigerte Prostaglandinsynthese MAP Kinase-gesteuert ist. Zur genaueren Aufklärung der beteiligten Faktoren und Wirkmechanismen müssen weitere Experimente erfolgen. Die klinische Relevanz weiterer Untersuchungen wird deutlich, wenn man bedenkt, dass der einzige therapeutische Ansatz der Salzverlusttubulopathien momentan die Hemmung der Prostaglandinsynthese darstellt. Es fehlen auch grundlegende Erkenntnisse über das COX-1/COX-2 Gleichgewicht im menschlichen Körper, welche für die Entwicklung weiterer Therapien notwendig sind. Mit dem Zellmodell konnten erste Regulationsmechanismen aufgedeckt werden, es eignet sich aber sicherlich auch dazu weitere Abläufe dieses Zellsystems näher zu untersuchen.

Bibliographie / References

1. Valentich JD, Stokols MF., An established cell line from mouse kidney medullary thick ascending limb. I. Cell culture techniques, morphology, and antigenic expression.
2. Kaji et al. Prostaglandin E2 inhibits Na-K-2Cl cotransport in medullary thick ascending limb cells. Am J Physiol. 1996; 271(1 Pt 1):C354-61.
3. Good DW, Caflisch CR, George T., Prostaglandin E2 regulation of ion transport is absent in medullary thick ascending limbs from SHR. Am J Physiol. 1995; 269(1 Pt 2):F47-54.
4. Macica CM, Yang Y, Herbert SC, Wang WH., Arachidonic acid inhibits activity of cloned renal K+ channel, ROMK1. Am J Physiol. 1996; 271(3 Pt 2):F588-94.
5. Yang T, Schnermann J, Briggs JP., Regulation of cyclooxygenase-2 expression in renal me-dulla by tonicity in vivo and in vitro. Am J Physiol. 1999; 277(46): F1-F9.
6. Persson AE, Ollerstam A, Liu R, Brown R., Mechanisms for macula densa cell release of renin. Acta Physiol Scand. 2004, 181(4): 471-474.
7. Gerber JG, Keller RT, and Nies AS., Prostaglandins and renin release: the effect of PGI2, PGE2, and 13,14-dihydro PGE2 on the baroreceptor mechanism of renin release in the dog. Circ Res 44: 796-799, 1979.
8. Trelle S, Reichenbach S, Wandel S, Hildebrand P., Cardiovascular safety of non- steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086 doi: 10.1136/bmj.c7086.
9. Schlatter E, Fröbe U, Greger R., Ion conductances of isolated cortical collecting duct cells. Pflugers Arch. 1992; 421(4):381-7.
10. Waldegger S, Jeck N, Barth P, Peters M, Vitzthum H, Wolf K, Kurtz A, Konrad M, Seyberth HW., Barttin increases surface expression and changes current properties of ClC-K channels. Pflugers Arch. 2002; 444(3):411-8.
11. Seyberth HW, Rascher W, Schweer H, Kühl PG, Mehl O, Scherer K., Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome. J Pediatr. 1985, 107: 694-701.
12. Yang T., Regulation of cyclooxygenase-2 in renal medulla. Acta Physiol Scand. 177: 417-421, 2003, Review.
13. Kömhoff M, Jeck NDM, Seyberth HW, Gröne HJ, Nüsing RM, Breyer MD., Cyclooxy-genase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int. 58: 2420-2425, 2000.
14. Nüsing RM, Reinalter SC, Peters M, Kömhoff M, Seyberth HW., Pathogenetic role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome: therapeutic use of the cyclooxygenase-2 inhibitor nimesulide. Clin Pharmacol Ther. 2001; 70(4):384-90.
15. Xu ZC, Yang Y, Hebert SC., Phosphorylation of the ATP-sensitive, inwardly rectifying K+ channel, ROMK, by cyclic AMP-dependent protein kinase. Journal Biological Chemistry.1996; 19;271(16):9313-9.
16. Lundgren DW, Moore RM, Collins PL, Moore JJ., Hypotonic stress increases cyclooxygenase-2 expression and prostaglandin release from amnion-derived WISH cells. J Biol Chem. 1997; 272(32):20118-24.
17. Uchida S., Physiological role of CLC-K1 chloride channel in the kidney. Nephrol Dial Transplant. 2000; 15 Suppl 6:14-5.
18. Kim HJ, Cui XS, Kim EJ, Kim WJ, Kim NH., New porcine microRNA genes found by homology search. Genom 2006; 49(10):1283-6.
19. Haas M, Forbush B 3rd., The Na-K-Cl cotransporter of secretory epithelia. Annu Rev. Physiol. 2000; 62:515-34.
20. Ling BN, Kokko KE, Eaton DC., Prostaglandin E2 activates clusters of apical Cl- channels in principal cells via a cyclic adenosine monophosphate-dependent pathway. J Clin Invest. 1994; 93(2):829-37.
21. Shoemaker L, Welch TR, Bergstrom W, Abrams SA, Yergey AL, Vieira N., Calcium kinetics in the hyperprostaglandin E syndrome. Pediatr Res. 1993; 33(1):92-6.
22. Konrad M, Leonhardt A, Hensen P, Seyberth HW, Köckerling A., Prenatal and postnatal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes. Pediatrics. 1999; 103(3):678-83.
23. Jensen BL, Stubbe J, Hansen PB, Andreasen D, Skøtt O., Localization of prostaglandin E(2) EP2 and EP4 receptors in the rat kidney. Am J Physiol Renal Physiol. 2001 Jun;280(6):F1001-9.
24. Friis UG, Stubbe J, Uhrenholt TR, Svenningsen P, Nüsing RM, Skøtt O, Jensen BL., Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells. Am J Physiol Renal Physiol. 2005 ; 289(5):F989-97.
25. Jensen BL, Schmid C, Kurtz A., Prostaglandins stimulate renin secretion and renin mRNA in mouse renal juxtaglomerular cells. Am J Physiol 271: F659-669, 1996.
26. Jans F, Vandenabeele F, Helbert M, Lambrichts I, Ameloot M, Steels P., A simple method for obtaining functionally and morphologically intact primary cultures of the medullary thick ascending limb of Henle's loop (MTAL) from rabbit kidneys. Pflugers Arch. 2000; 440(4):643-51.
27. Morath R, Klein T, Seyberth HW, Nüsing RM., Immunolocalization of the four prostaglandin E2 receptor proteins EP1, EP2, EP3, and EP4 in human kidney. J Am Soc Nephrol. 1999; 10(9):1851-60.
28. Seyberth HW, Königer SJ, Rascher W, Kühl PG, Schweer H., Role of prostaglandins in hyperprostaglandin E syndrome and in selected renal tubular disorders. Pediatr Nephrol. 1987;1(3):491-7.
29. Woo JG, Park SY, Lim JC, Joo MJ, Kim HR, Sohn UD., Acid-induced COX-2 expression and prostaglandin E2 production via activation of ERK1/2 and p38 MAPK in cultured feline esophageal smooth muscle cells. Arch Pharm Res. 2011;34(12):2131- 40.
30. Abb. 1 Schematische Darstellung NKCC2-Transporter 12
31. Abb. 3 Laufstrecke in cm in Bezug auf die Proteingröße in kDa 31
32. Abb. 5 Positiver Nachweis des THP unter dem Fluoreszenzmikroskop 39
33. Abb. 7 mRNA der Ionenkanäle NKCC2, ROMK und als Rederenzwert ß-Actin 41
34. Abb. 8 mRNA des Enzyms PGES-1 und von COX-1 und COX-2
35. Gitelman HJ, Graham JB, Welt LG., A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians. 1966, 79: 221-223.
36. Ohlsson A, Sieck U, Cumming W, Akhtar M, Serenius F., A variant of Bartter's syndrome. Bartter's syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta Paediatr Scand. 1984; 73(6):868-74.
37. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP., Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet. 1996; 13(2):183-8.
38. Peco-Antic A, Dudic S, Marsenic O, Zivic G., Bartter's syndrome: new classification, old therapy. Srp Arh Celok Lek. 2001; 129(5-6):139-42.
39. Hebert SC., Bartter syndrome. Curr Opin Nephrol Hypertens. 12: 527-532, 2003.
40. Proesmans W, Devlieger H, Van Assche A, Eggermont E, Vandenberghe K, Lemmens F, Sieprath P, Lijnen P., Bartter syndrome in two siblings--antenatal and neonatal observations. Int J Pediatr Nephrol. 1985; 6(1):63-70.
41. Guggino SE, Guggino WB, Green N, Sacktor B., Ca2+-activated K+ channels in cultured medullary thick ascending limb cells. Am J Physiol. 1987; 252(2 Pt 1):C121-7.
42. Cl cotransporter by macula densa and thick ascending limb cells of rat and rabbit nephron. J Clin Invest. 1996; 98(3):635-40.
43. Thoren S, Jakobsson P. J., Coordinate up-and down-regulation of glutathione- dependent prostaglandin E synthase and cyclooxygenase-2 in A549 cells. Inhibition by NS-398 and leukotriene C4. Eur J Biochem 2000; 267, 6428-34.
44. Vane JR, Bakhle YS, Botting RM., Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998, 38: 97-120.
45. Peskar BA., Derivate des Arachidonsäurestoffwechsels. Allg. und spez. Pharmakologie und Toxikologie, Forth/Henschler/Rumml (eds), Urban-Fischer-Verlag, Aufl.8: 381- 392, 2001.
46. Joos H, Albrecht W, Laufer S, Brenner RE., Differential effects of p38MAP kinase inhibitors on the expression of inflammation-associated genes in primary, interleukin- 1beta-stimulated human chondrocytes. Br J Pharmacol. 2010;160(5):1252-62.
47. Lytle C, Xu JC, Biemesderfer D, Forbush B 3rd., Distribution and diversity of Na-K- Cl cotransport proteins: a study with monoclonal antibodies. Am J Physiol. 1995; 269(6
48. Howard MJ, Insel PA., Elevated extracellular K+ enhances arachidonic acid release in MDCK-D1 cells. Am J Physiol. 1990; 259(2 Pt 1):C224-31.
49. Ichijo H., From receptors to stress-activated MAP kinases. Oncogene. 1999; 18(45):6087-93.
50. Seyberth HW., How can you differentiate neonatal Bartter's syndrome from hyperprostaglandin (-uria) E2 syndrome? Pediatr Nephrol. 1994; 8(4):407.
51. Watts BA 3rd, Di Mari JF, Davis RJ, Good DW., Hypertonicity activates MAP kinases and inhibits HCO-3 absorption via distinct pathways in thick ascending limb.
52. Kim JA, Sheen MR, Lee SD, Jung JY, Kwon HM., Hypertonicity stimulates PGE2 signaling in the renal medulla by promoting EP3 and EP4 receptor expression. Kidney Int. 2009;75(3):278-84.
53. Jeck N, Reinalter SC, Henne T, Marq W, Mallmann R, Pasel K, Vollmer M, Klaus G, Leonhardt A, Seyberth HW, Konrad M., Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics. 2001; 108(1):E5.
54. Vane JR., Inhibition of prostaglandin synthesis as a mechanism of action for aspirin- like drugs. Nat New Biol. 1971 23;231(25):232-5.
55. Mount DB, Baekgaard A, Hall AE, Plata C, Xu J, Beier DR, Gamba G, Hebert SC., Isoforms of the Na-K-2Cl cotransporter in murine TAL I. Molecular characterization and intrarenal localization. Am J Physiol. 1999; 276(3 Pt 2):F347-58.
56. Xu JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, Hebert SC., Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am J Physiol. 1997; 273(5 Pt 2):F739-48.
57. Shankar SS, Brater DC., Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol. 2003; 284(1):F11-21.
58. Frindt, G., Low-conductance K channels in apical membrane of rat cortical collecting tubule. Am J Physiology. 1989; 256(1 Pt 2):F143-51.
59. Persson AE, Salomonsson M, Westerlund P, Greger R, Schlatter E, Gonzalez E., Macula densa function. Kidney Int. 32: 39-44, 1991.
60. Zhou X, Wingo CS., Mechanisms of rubidium permeation by rabbit cortical collecting duct during potassium restriction. Am J Physiol. 1992; 263(6 Pt 2):F1134-41.
61. Mc Nicholas CM, Yang Y, Giebisch G, Herbert SC., Molecular site for nucleotide binding on an ATP-sensitive renal K+ channel (ROMK2). Am Journal Physiology 1996; 271(2 Pt 2):F275-85.
62. Marlow N, Chiswick ML., Neonatal Bartter's syndrome, indomethacin and necrotising enterocolitis. Acta Paediatr Scand. 1982; 71(6):1031-2.
63. Rosenbaum P, Hughes M., Persistent, probably congenital, hypokalemic metabolic alkalosis with hyaline degeneration of renal tubules and normal urinary aldosteron. Am J Dis Child 94:560, 1957.
64. Reinalter SC, Jeck N, Peters M, Seyberth HW., Pharmacotyping of hypokalaemic salt-losing tubular disorders. Acta Physiol Scand. 2004;181(4):513-21.
65. Giebisch, G., pH-dependent modulation of the cloned renal K+ channel, ROMK. Am J Physiology 1998; 275(6 Pt 2):F972-81.
66. Payne JA, Xu JC, Haas M, Lytle CY, Ward D, Forbush B 3rd., Primary structure, functional expression, and chromosomal localization of the bumetanide-sensitive Na-K- Cl cotransporter in human colon. J Biol Chem. 1995; 270(30):17977-85.
67. Wang WH, Schwab A, Giebisch G., Regulation of small-conductance K+ channel in apical membrane of rat cortical collecting tubule. Am J Physiol. 1990; 259(3 Pt 2):F494-502.
68. Reinalter SC, Jeck N, Brochhausen C, Watzer B, Nüsing RM, Seyberth HW, Kömhoff M., Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int. 2002; 62(1):253-60.
69. Francois H, Facemire C, Kumar A, Audoly L, Koller B, Coffman T., Role of microsomal prostaglandin E synthase 1 in the kidney. J Am Soc Nephrol. 2007;18(5):1466-75.
70. Russel JM., Sodium-potassium-chloride cotransport. Physiol Rev. 2000; 80(1):211-76.
71. Thoren S, Weinander R, Saha S, Jegerschold C, Pettersson PL, Samuelsson B, Hebert H, Hamberg M, Morgenstern R, Jakobsson P. J., Human microsomal prostaglandin E synthase-1: purification, functional characterization, and projection structure determination. J Biol Chem 2003 278, 22199-209.
72. Schröter J, Timmermanns G, Seyberth HW, greven J, Bachmann S., Marked reduction of Tamm-Horsfall protein synthesis in hyperprostaglandin E-syndrome.
73. Guan Z, Buckman SY, Pentland AP, Templeton DJ, Morrison AR., Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway. J Biol Chem. 1998 May 22;273(21):12901-8.
74. Peters M, Jeck N, Seyberth HE, Konrad M., Hereditary hypokalemic salt-losing tubulopathies: Bartter-like syndromes. Contrib Nephrol. 2001; (136):157-73.
75. Naesens M, Steels P, Verberckmoes R, Vanrenterghem Y, Kuypers D., Bartter's and Gitelman's syndromes: from gene to clinic. Nephron Physiol. 2004;96(3):p65-78.
76. Seyberth HW., An improved terminology and classification of Bartter-like syndromes.
77. Kömhoff M, Reinalter SC, Gröne HJ, Seyberth HW., Induction of microsomal prostaglandin E2 synthase in the macula densa in children with hypokalemic salt-losing tubulopathies. Pediatr Res. 2004;55(2):261-6.
78. Zhang F, Warskulat U, Wettstein M, Schreiber R, Henninger HP, Decker K, Häussinger D., Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat liver macrophages. Biochem J. 1995 Nov 15; 312 ( Pt 1):135-43.
79. Kiriyama M, Ushikubi F, Kobayashi T, Hirata M, Sugimoto Y, Narumiya S., Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. Br J Pharmacol. 1997; 122(2):217- 24.
80. Lawrence RA, Jones RL, Wilson LH., Characterization of receptors involved in the direct and indirect actions of prostaglandins E and I on the guinea-pig ileum. Br J Pharmacol. 1992; 105(2):271-8.
81. Jakobsson P. J, Thoren S, Morgenstern R. & Samuelsson B., Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A 1999 96,7220-5.
82. Grotjohann I, Gitter AH, Köckerling A, Bertog M, Schulzke JD, Fromm M., Localization of cAMP-and aldosterone-induced K+ secretion in rat distal colon by conductance scanning. J Physiol. 1998; 507 ( Pt 2):561-70.
83. Okuda T, Kojima I, Ogata E, Kurokawa K., Ambient C1-ions modify rat mesangial cell contraction by modulating cell inositol trisphosphate and Ca2+ via enhanced prostaglandin E2. J Clin Invest. 1989; 84(6):1866-72.
84. Stokes JB., Effect of prostaglandin E2 on chloride transport across the rabbit thick ascending limb of Henle. Selective inhibitions of the medullary portion. J Clin Invest. 1979; 64(2):495-502.
85. Stokes JB, Kokko JP., Inhibition of sodium transport by prostaglandin E2 across the isolated, perfused rabbit collecting tubule. J Clin Invest. 1977 Jun; 59(6):1099-104.
86. McKenzie JK, McQueen EG., Immunofluorescent localization of Tamm-Horsfall mucoprotein in human kidney. J Clin Pathol. 1969; 22(3):334-9.
87. Wang WH, Giebisch G., Dual modulation of renal ATP-sensitive K+ channel by protein kinases A and C. Proc Natl Acad Sci USA. 1991; 1;88(21):9722-5.
88. Long CR, Kinoshita Y, Knox FG., Prostaglandin E2 induced changes in renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat. Prostaglandins. 1990; 40(6):591-601.
89. Nantel N, Meadows E, Denis D, Connolly B, Metters K, Giaid A., Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly. FEBS Lett. 457: 475-477, 1999.
90. Kammerl MC, Nüsing RM, Seyberth HW, Riegger GA, Kurtz A, Krämer BK., Inhibition of cyclooxygenase-2 attenuates urinary prostanoid excretion without affecting renal renin expression. Pflugers Arch. 2001; 442(6):842-7.

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten