Clinical Investigation

Kidney International (1993) 44, 401–410; doi:10.1038/ki.1993.258

Marked reduction of Tamm-Horsfall protein synthesis in hyperprostaglandin E-syndrome

Jens Schröter1, Gundi Timmermans1, Hansjörg W Seyberth1, Jürgen Greven1 and Sebastian Bachmann1

1Department of Anatomy and Cell Biology, University of Heidelberg; Children's Hospital, University of Marburg; Department of Pharmacology, University of Aachen; Germany

Correspondence: Priv Doz Dr Sebastian Bachmann, Institut für Anatomie und Zellbiologie 1, Universität Heidelberg, Im Neuenheimer Feld 307, D-6900 Heidelberg, Germany.

Received 21 December 1992; Revised 12 April 1993; Accepted 12 April 1993.

Top

Abstract

Marked reduction of Tamm-Horsfall protein synthesis in hyperprostaglandin E-syndrome. Hyperprostaglandin E-syndrome (HPS), a recently described variant of Bartter's syndrome (BS), resembles BS in a number of symptoms but is distinct from BS in others. Similar to BS, HPS is characterized by congenital hypokalemic alkalosis, hypertrophy of the juxtaglomerular apparatus, hyperreninemia, secondary hyperaldosteronism, normal blood pressure and renal diabetes insipidus. Other than BS, HPS is constantly associated with chronic hypercalciuria and nephrocalcinosis as well as both renal and systemic PGE2 overproduction. Correction of most of the symptoms in HPS is achieved by permanent inhibition of prostaglandin synthesis with indomethacin. Among the causes leading to HPS, a selective damage of the distal tubule in HPS has been suggested. Therefore, synthesis of Tamm-Horsfall protein (THP), a glycoprotein exclusively produced in the thick ascending limb of the loop of Henle, was measured by ELISA in the urine of seven infant HPS patients (aged 3 to 8 years). Patients were investigated both under constant indomethacin treatment and after a one week period without indomethacin. Nine healthy children (aged 5 months to 10 years) served as controls. In controls mean daily THP excretion was 54.2 plusminus 13.9 (median 46.0) mg/24 hr/1.73 m2 whereas in HPS, THP levels were strongly diminished. During withdrawal of indomethacin treatment, mean THP level was 12.7 plusminus 10.1 (median 7.2) mg/24 hr/1.73 m2 and 10.3 plusminus 10.1 (median 3.5) mg/24 hr/1.73 m2 under indomethacin treatment, respectively. THP excretion values both without indomethacin and under indomethacin treatment were significantly different from controls (P less than or equal to 0.005); however, there was no significant difference between the THP levels during or after cessation of indomethacin treatment. Creatinine clearance in HPS patients was 75.1 plusminus 15.9 (median 76.2) ml/min/1.73 m2 without indomethacin and 81.9 plusminus 15.1 (median 83.0) ml/min/1.73 m2 under indomethacin treatment. Control values were not obtained. Comparative measurements of THP excretion in six classical BS-patients (aged 3 months to 17 years) revealed normal THP values in two individuals and intermediate levels in the others: the mean level of six BS patients was 30.8 plusminus 13.5 (median 25.0) mg/24 hr/1.73 m2 and was thus significantly higher than in HPS both with and without indomethacin treatment (P less than or equal to 0.05). Immunohistochemistry in renal biopsies of three of the HPS patients showed a strong reduction of cortical tubular THP immunoreactivity in two cases and a less pronounced reduction in the third. In situ hybridization using a THP-riboprobe in these three biopsies revealed significantly reduced or absent THP-mRNA levels. The severely decreased THP-production supports previous assumptions that one of the major causes underlying HPS is a selective congenital defect of the distal tubule. Differences in THP excretion between HPS and BS support a concept that defines HPS and BS as separate entities with a number of similarities.

Top

References

  1. Bartter FC, Pronove P, Gill JR Jr, MacCardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33:811–828, 1962 | Article | PubMed | ISI | ChemPort |
  2. Stein JH: The pathogenetic spectrum of Bartter's syndrome. Kidney Int 28:85–93, 1985 | PubMed | ChemPort |
  3. Fanconi A, Schachenmann G, Nüssli R, Prader A: Chronic hypokalemia with growth retardation, normotensive hyperrenin-hyperaldosteronism ("Bartter's syndrome") and hypercalciuria. Helv Paed Acta 26:144–163, 1971
  4. Seyberth HW, Rascher W, Schweer H, Kühl PG, Mehls O, Schärer K: Congenital hypokalemia with hypercalciuria in preterm infants: A hyperprostaglandinuric tubular syndrome different from Bartter syndrome. J Pediatr 107:694–701, 1985 | PubMed | ISI | ChemPort |
  5. Taugner R, Waldherr R, Seyberth HW, Erdös EG, Menard J, Schneider D: The juxtaglomerular apparatus in Bartter's syndrome and related tubulopathies. Virchows Arch 412:459–470, 1988
  6. Seyberth HW, Königer SJ, Schweer H: Hyperprostaglandin E2 syndrome: A congenital tubular disorder with a complex clinical presentation, in Physiological Foundation in Perinatal Care, edited by Stern L, Amsterdam, Elsevier, 1987, pp. 302–307
  7. Hufnagle KG, Khan SN, Penn D, Cacciarelli A, Williams P: Renal calcifications: A complication of long-term furosemide therapy in preterm infants. Pediatrics 70:360–363, 1982 | PubMed | ISI | ChemPort |
  8. Thornley C, Dawnay A, Cattell WR: Human Tamm-Horsfall glycoprotein: Urinary and plasma levels in normal subjects and patients with renal disease determined by a fully validated radioimmunoassay. Clin Sci 68:529–535, 1985 | PubMed |
  9. Hoyer JR, Seiler MW: Pathophysiology of Tamm-Horsfall protein. Kidney Int 16:279–289, 1979 | PubMed | ISI | ChemPort |
  10. Bachmann S, Koeppen-Hagemann I, Kriz W: Ultrastructural localization of Tamm-Horsfall glycoprotein (THP) in rat kidney as revealed by protein A-gold immunocytochemistry. Histochemistry 83:531–538, 1985 | Article | PubMed | ISI | ChemPort |
  11. Bachmann S, Metzger R, Bunnemann B: Tamm-Horsfall protein-mRNA synthesis is localized to the thick ascending limb of Henle's loop in rat kidney. Histochemistry 94:517–523, 1990 | Article | PubMed | ISI | ChemPort |
  12. Hunt JS, McGiven AR, Groufsky A, Lynn KL, Taylor MC: Affinity purified antibodies of defined specificity for use in a solid-phase microplate radioimmunoassay of human Tamm-Horsfall glycoprotein in urine. Biochem J 227:957–963, 1985 | PubMed | ISI | ChemPort |
  13. Hoyer JR, Sisson SP, Vernier RL: Tamm-Horsfall glycoprotein. Ultrastructural immunoperoxidase localisation in rat kidney. Lab Invest 41:168–173, 1979 | PubMed | ISI | ChemPort |
  14. Greven J, Kölling B, Bronewski-Schwarzer B: Evidence for a role of the Tamm-Horsfall protein in the tubular action of furosemide-like loop diuretics, in Diuretics, edited by Puschett JB, New York, Elsevier, 1984, pp. 203–214
  15. Wirdnam PK, Milner RDG: Tamm-Horsfall glycoprotein release from rat kidney cortex slices in vitro. Clin Sci 67:529–534, 1984 | PubMed | ChemPort |
  16. Bachmann S, Dawnay A, Bouby N, Bankir L: Tamm-Horsfall protein excretion during chronic alterations in urinary concentration and protein intake in the rat. Renal Physiol Biochem 14:236–245, 1991 | PubMed | ChemPort |
  17. Dulawa J, Jann K, Thomsen M, Rambausek M, Ritz E: Tamm-Horsfall glycoprotein interferes with bacterial adherence to human kidney cells. Eur J Clin Invest 18:87–91, 1988 | PubMed | ISI | ChemPort |
  18. Hession C, Decker JM, Sherblom AP, Kumar S, Yue CC, Mattaliano RJ, Tizard R, Kawashima E, Schmeissner U, Heletky S, Chow EP, Burne CA, Shaw A, Muchmore AV: Uromodulin (Tamm-Horsfall glycoprotein): A renal ligand for lymphokines. Science 237:1479–1484, 1987 | PubMed | ISI | ChemPort |
  19. Hess B, Nakagawa Y, Parks JH, Coe FL: Molecular abnormality of Tamm-Horsfall glycoprotein in calcium oxalate nephrolithiasis. Am J Physiol 260:F569–F578, 1991 | PubMed | ISI | ChemPort |
  20. Rambausek M, Dulawa J, Jann K, Ritz E: Tamm-Horsfall glycoprotein in diabetes mellitus: Abnormal chemical composition and colloid stability. Eur J Clin Invest 18:237–242, 1988 | PubMed |
  21. Tamm I, Horsfall FL: Characterisation and separation of an inhibitor of viral haemagglutination present in urine. Proc Soc Exp Biol Med 74:108–114, 1950 | ISI | ChemPort |
  22. Dawnay A, Thornley C, Cattell WR: An improved radioimmunoassay for urinary Tamm-Horsfall glycoprotein. Biochem J 206:461–465, 1982 | PubMed |
  23. Müller H, Mrongovius R, Seyberth HW: Improved sample preparation for the quantitative mass spectrometric determination of prostaglandins in biological samples. J Chromatogr 226:450–454, 1981
  24. Seyberth HW, Tulassay T, Kühl PG, Soeding K, Rascher W, Schweer H: Excretion of primary prostanoids and their metabolites during acute volume expansion. Prostaglandins 35:221–232, 1988
  25. Seyberth HW, Sweetman BJ, Frölich JC, Oates JA: Quantification of the major urinary metabolite of the E prostaglandins by mass spectrometry: Evaluation of the method's application to clinical studies. Prostaglandins 11:381–397, 1976 | Article | PubMed | ISI | ChemPort |
  26. Grant AMS, Baker LRI, Neuberger A: Urinary Tamm-Horsfall glycoprotein in certain kidney diseases and its content in renal and bladder calculi. Clin Sci 44:377–384, 1973 | PubMed |
  27. Richet G: The mechanism of action of some loop-acting diuretics—Role of a binding to Tamm-Horsfall protein. Clin Nephrol 19:S42–S44, 1983
  28. Budi-Santoso AW, Scott DM, Kinne R: Localization of Tamm-Horsfall protein in chloride transporting epithelia: Lack of correlation with the Na, K, Cl-cotransporter. Eur J Cell Biol 43:104–109, 1987
  29. Greger R: Ion transport mechanisms in thick ascending limb of Henle's loop of mammalian nephron. Physiol Rev 65:760–796, 1985 | PubMed | ISI | ChemPort |
  30. Fujita T, Sakaguchi H, Shibagaki M, Fukui T, Nomura M, Sekiguchi S: The pathogenesis of Bartter's syndrome: Functional and histological studies. Am J Med 63:467–474, 1977
  31. Gill JR, Bartter FC: Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter's syndrome. Am J Med 65:766–772, 1978 | Article | PubMed | ISI | ChemPort |
  32. Jamison RL, Ross JC, Kempson RL, Sufit CR, Parker TE: Surreptitious diuretic ingestion and pseudo-Bartter's syndrome. Am J Med 73:142–147, 1982
  33. Jacinto JS, Modanlou HD, Crade M, Strauss AA, Bosu SK: Renal calcification incidence in very low birth weight infants. Pediatrics 81:31–35, 1988 | PubMed | ISI | ChemPort |
  34. Lee JB, Katayama S: Direct stimulation of renal prostaglandin E2 by furosemide. Adv Prostagland Thrombox Leukotr Res 15:451–453, 1985
  35. Hänze S, Seyberth HW: Untersuchungen zur Wirkung der Diuretika Furosemid, Ethacrynsäure und Triamteren auf die renale Magnesium-und Calciumausscheidung. Klin Wochenschr 45:313–314, 1967
  36. Bachmann S: Tamm Horsfall-Protein bei der Ratte. Immuncytochemische Lokalisation und Ausscheidung unter verschiedenen Bedingungen. Habilitationsschrift, Heidelberg, 1990
  37. Lynn KL, Shenkin A, Marshall RD: Factors affecting excretion of human urinary Tamm-Horsfall glycoprotein. Clin Sci 62:21–26, 1982
  38. Rosen S, Greenfeld Z, Bernheim J, Rathaus M, Podjarny E, Brezis M: Hypercalcemie nephropathy: Chronic disease with predominant medullary inner stripe injury. Kidney Int 37:1067–1075, 1990
  39. Leonhardt A, Timmermanns G, Roth B, Seyberth HW: Calcium homeostasis and hypercalciuria in hyperprostaglandin E-syndrome. J Pediatr 120:546–554, 1992 | PubMed | ChemPort |
  40. Mené P, Dunn MJ: Vascular, glomerular and tubular effects of angiotensin II, kinins and prostaglandins, in The Kidney, edited by Seldin DW, Giebisch G, New York, Raven Press, 1992, pp. 1205–1248
  41. Lemley KV, Schmitt SL, Holliger C, Dunn MJ, Robertson CR, Jamison RL: Prostaglandin synthesis inhibitors and vasa recta erythrocyte velocities in the rat. Am J Physiol 247:F562–F567, 1984

Extra navigation

.
ADVERTISEMENT