Abstract
Hyperprostaglandin E syndrome (HPS), the prenatal variant of Bartter's syndrome, is characterized by a marked and selective stimulation of prostaglandin E (PGE2) synthesis. In the study group HPS patients showed increased urinary levels of PGE2, an index of renal, and of 11α-hydroxy-9,15-dioxo-2,3,4,5,20-pentanor-19-carboxyprostanoic acid(PGE-M), an index of systemic PGE2 synthesis of 470% and of 570%, respectively. In addition, plasma concentration of PGE-M was also elevated 6.3-fold when compared with a control group. The urinary levels of other prostanoids were unaltered. During indomethacin treatment in both groups prostanoid excretion rates were suppressed to similar levels. To investigate the origin of stimulated prostanoid biosynthesis in HPS patients CD14+ monocytes were isolated from plasma samples, and the prostanoid synthesis was analyzed. The pattern and amounts of metabolites synthesized from endogenous arachidonic acid pools did not vary significantly between monocytes of the HPS and the control group. Thromboxane A2 (TXA2) was formed as the major prostanoid product. Using PGH2 as an exogenous substrate, again no difference in PGE2 biosynthesis was observed, indicating no difference in PGE-synthetic activity between both groups. Additionally, mRNA expression analysis of CD14+ monocytes via RT-PCR delineated the constitutive expression of cyclooxygenase-1, cyclooxygenase-2, and thromboxane synthase mRNA in cells from HPS patients and controls without statistical differences between these two groups. In conclusion, our data show that monocytes are not the source for the increased PGE2 biosynthesis in children with HPS, and a genetic defect in PGE synthesis can be excluded as the primary event in the pathogenesis in HPS.
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Abbreviations
- CD:
-
cluster of differentiation
- GC-MS/MS:
-
gas chromatography-tandem mass spectrometry
- HPS:
-
hyperprostaglandin E syndrome
- PG:
-
prostaglandin
- PGE-M:
-
11α-hydroxy-9,15-dioxo-2,3,4,5,20-pentanor-19-carboxyprostanoic acid
- TX:
-
thromboxane
References
Seyberth HW, Königer SJ, Rascher W, Kühl PG, Schweer H 1987 Role of prostaglandins in hyperprostaglandine E syndrome and in selected renal tubular disorders. Pediatr Nephrol 1: 491–497.
Seidel C, Reinalter S, Seyberth HW, Schärer K 1995 Pre-pubertal growth in the hyperprostaglandin E syndrome. Pediatr Nephrol 9: 723–728.
Fanconi A, Schachenmann G, Nüssli R, Prader A 1971 Chronic hypokalaemia with growth retardation, normotensive hyperrenin-hyperaldosteronism (“Bartter's syndrome”), and hypercalciuria. Helv Paediatr Acta 2: 144–163.
McCredie DA, Rotenberg E, Williams AL 1974 Hypercalciuria in potassium-loosing nephropathy: a variant of Bartter's syndrome. Aust Paediatr J 10: 186–295.
Proesmans W, Devlieger H, Van Assche A, Eggermont E, Vandenberghe K, Lemmens F, Sieprath P, Lijnen P 1985 Bartter syndrome in two siblings-antenatal and neonatal observations. Int J Pediatr Nephrol 6: 63–70.
Seyberth HW, Rascher W, Schweer H, Kühl PG, Mehls O, Schärer K 1985 Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome. J Pediatr 107: 694–701.
Dillon M, Shah V, Mitchell MD 1979 Bartter's syndrome: 10 cases in childhood. Q J Med 191: 429–446.
Proesmans W, Massa G, Vanderschueren-Lodeweyckx M 1988 Growth from birth to adulthood in a patient with the neonatal from of Bartter syndrome. Pediatr Nephrol 2: 205–209.
Otto JC, Smith WL 1995 Prostaglandin endoperoxide synthases-1 and -2. J Lipid Mediat Cell Signal 12: 139–156.
Rane A, Oelz O, Frölich JC, Seyberth HW, Sweetman BJ, Watson JT, Wilkinsom GR, Oates JA 1978 Relationship between plasma concentration by indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man. Clin Pharmacol Ther 23: 658–668.
Nüsing R, Ullrich V 1992 Regulation of cyclooxygenase and thromboxane synthase in human monocytes. Eur J Biochem 206: 131–136.
Schweer H, Watzer B, Seyberth HW 1994 Determination of seven prostanoids in 1 mL of urine by gas chromatography-negative ion chemical ionization triple stage quadrupole mass spectrometry. J Chromatogr 652: 221–227.
Seyberth HW, Knapp G, Wolf D, Ulmer HE 1983 Introduction of plasma indomethacin level monitoring and evaluation of an effective threshold level in very low birth weight infants with symptomatic patent ductus arteriosus. Eur J Pediatr 141: 71–79.
Chomczynski P, Sacchi N 1987 Single-step method of RNA isolation by acid guanidine thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159.
Klein T, Nüsing RM, Pfeilschifter J, Ullrich V 1994 Selective inhibition of cyclooxygenase 2. Biochem Pharmacol 48: 1605–1610.
Nüsing RM, Mohr S, Ullrich V 1995 Activin A and retinoic acid synergize in cyclooxygenase-1 and thromboxane synthase induction during differentiation of J774.1 macrophages. Eur J Biochem 227: 130–136.
Schweer H, Kammer J, Kühl PG, Seyberth HW 1986 Determination of peripheral plasma prostanoid concentration: an unreliable index of “in vivo” prostanoid activity. Eur J Clin Pharmacol 31: 303–305.
Seyberth HW, Soergel M, Köckerling A 1997 Hypokalaemic tubular disorders: the hyperprostaglandin E syndrome and the Gitelman-Bartter syndrome. In: Davison AM, Cameron JS, Grünfeld J-P, Kerr DNS, Ritz E (eds) Oxford Textbook of Clinical Nephrology. Oxford University Press, Oxford, pp 1085–1094.
O'Neill GP, Ford-Hutchinson AW 1993 Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 330: 156–160.
Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD 1994 Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94: 2504–2510.
Simon DB, Karet FE, Hamdan JM, Dipietro A, Sanjad SA, Lifton RP 1996 Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 13: 183–188.
Simon DB, Karet FE, Rodriguezsoriano J, Hamdan JH, Dipietro A, Trachtman H, Sanjad SA, Lifton RP 1996 Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14: 152–156.
Smith WL, Bell TG 1978 Immunohistochemical localization of the prostaglandinforming cyclooxygenase in renal cortex. Am J Physiol 235:F451–F457.
Breyer MD, Badr KF 1996 Arachidonic acid metabolites and the kidney. In: Brenner MB (ed) The Kidney. WB Saunders, Philadelphia, pp 754–788.
Nüsing RM, Klein T, Pfeilschifter J, Ullrich V 1996 Effect of cyclic AMP and prostaglandin E(2) on the induction of nitric oxide- and prostanoid-forming pathways in cultured rat mesangial cells. Biochem J 313: 617–623.
Markey CM, Alward A, Weller PE, Marnett LJ 1987 Quantitative studies of hydroperoxide reduction by prostaglandin H synthase. J Biol Chem 262: 6266–6279.
Acknowledgements
The authors thank S. Mahr and B. Watzer for technical assistance in the GC-MS/MS analysis and S. Noll for organization of the control group.
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Supported by grants of the Deutsche Forschungsgemeinschaft (Se 263/11-1, Nu 73/2-1) and by the Stiftung P.E. Kempkes.
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Nüsing, R., Schaub, T., Klein, T. et al. Prostanoid Biosynthesis by Blood Monocytes of Children with Hyperprostaglandin E Syndrome. Pediatr Res 42, 241–246 (1997). https://doi.org/10.1203/00006450-199708000-00019
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DOI: https://doi.org/10.1203/00006450-199708000-00019
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