Skip to main content
SpringerLink
Log in

Calcium oxalate monohydrate aggregation induced by aggregation of desialylated Tamm-Horsfall protein

  • Original Paper
  • Published:
Urological Research Aims and scope Submit manuscript

Abstract

Tamm-Horsfall protein (THP) is thought to protect against calcium oxalate monohydrate (COM) stone formation by inhibiting COM aggregation. Several studies reported that stone formers produce THP with reduced levels of glycosylation, particularly sialic acid levels, which leads to reduced negative charge. In this study, normal THP was treated with neuraminidase to remove sialic acid residues, confirmed by an isoelectric point shift to higher pH. COM aggregation assays revealed that desialylated THP (ds-THP) promoted COM aggregation, while normal THP inhibited aggregation. The appearance of protein aggregates in solutions at ds-THP concentrations ≥1 μg/mL in 150 mM NaCl correlated with COM aggregation promotion, implying that ds-THP aggregation induced COM aggregation. The aggregation-promoting effect of the ds-THP was independent of pH above its isoelectric point, but was substantially reduced at low ionic strength, where protein aggregation was much reduced. COM aggregation promotion was maximized at a ds-THP to COM mass ratio of ~0.025, which can be explained by a model wherein partial COM surface coverage by ds-THP aggregates promotes crystal aggregation by bridging opposing COM surfaces, whereas higher surface coverage leads to repulsion between adsorbed ds-THP aggregates. Thus, desialylation of THP apparently abrogates a normal defensive action of THP by inducing protein aggregation, and subsequently COM aggregation, a condition that favors kidney stone formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bayer ME (1964) An electron microscope examination of urinary mucoprotein and its interaction with influenza virus. J Cell Biol 21:265–274

    Article  PubMed  CAS  Google Scholar 

  2. Benkovic J, Furedi-Milhofer H, Hlady V, Cvoriscec D, Stavljenic-Rukavina A (1995) Effect of Tamm-Horsfall protein on calcium oxalate precipitation. Eur J Clin Chem Clin Biochem 33:705–710

    PubMed  CAS  Google Scholar 

  3. Bichler K, Mittermuller B, Strohmaier WL, Feil G, Eipper E (1999) Excretion of Tamm-Horsfall protein in patients with uric acid stones. Urol Int 62:87–92

    Article  PubMed  CAS  Google Scholar 

  4. Boeve ER, Cao LC, de Bruijn WC, Robertson WG, Romijn JC, Schroder FH (1994) Zeta potential distribution on calcium oxalate crystal and Tamm-Horsfall protein surface analyzed with Doppler electrophoretic light scattering. J Urol 152:531–536

    PubMed  CAS  Google Scholar 

  5. Boyce WH, King JS Jr (1963) Present concepts concerning the origin of matrix and stones. Ann NY Acad Sci 104:563–578

    Article  PubMed  CAS  Google Scholar 

  6. Boyce WH, Swanson M (1955) Biocolloids of urine in health and in calculous disease. II. Electrophoretic and biochemical studies of a mucoprotein insoluble in molar sodium chloride. J Clin Invest 34:1581–1589

    Article  PubMed  CAS  Google Scholar 

  7. Canales BK, Anderson L, Higgins L, Slaton J, Roberts KP, Liu N, Monga M (2008) Second prize: comprehensive proteomic analysis of human calcium oxalate monohydrate kidney stone matrix. J Endourol 22:1161–1167

    Article  PubMed  Google Scholar 

  8. Cao LC, Deng G, Boeve ER, de Bruijn WC, de WR, Verkoelen CF, Romijn JC, Schroder FH (1996) Zeta potential measurement and particle size analysis for a better understanding of urinary inhibitors of calcium oxalate crystallization. Scanning Microsc 10:401–411

    Google Scholar 

  9. Cavallone D, Malagolini N, Serafini-Cessi F (2001) Mechanism of release of urinary Tamm-Horsfall glycoprotein from the kidney GPI-anchored counterpart. Biochem Biophys Res Commun 280:110–114

    Article  PubMed  CAS  Google Scholar 

  10. Clyne DH, Kant KS, Pesce AJ, Pollak VE (1979) Nephrotoxicity of low molecular weight serum proteins: physicochemical interactions between myoglobin, hemoglobin, Bence-Jones proteins and Tamm-Horsfall mucoprotein. Curr Probl Clin Biochem 9:299–308

    Google Scholar 

  11. Clyne DH, Pesce AJ, Thompson RE (1979) Nephrotoxicity of Bence Jones proteins in the rat: importance of protein isoelectric point. Kidney Int 16:345–352

    Article  PubMed  CAS  Google Scholar 

  12. De Yoreo JJ, Qiu SR, Hoyer JR (2006) Molecular modulation of calcium oxalate crystallization. Am J Physiol Renal Physiol 291:F1123–F1131

    Article  PubMed  Google Scholar 

  13. Finlayson B (1978) Physicochemical aspects of urolithiasis. Kidney Int 13:344–360

    Article  PubMed  CAS  Google Scholar 

  14. Ganter K, Bongartz D, Hesse A (1999) Tamm-Horsfall protein excretion and its relation to citrate in urine of stone-forming patients. Urology 53:492–495

    Article  PubMed  CAS  Google Scholar 

  15. Gokhale JA, Glenton PA, Khan SR (1997) Biochemical and quantitative analysis of Tamm-Horsfall protein in rats. Urol Res 25:347–354

    Article  PubMed  CAS  Google Scholar 

  16. Grover PK, Resnick MI (1995) Evidence for the presence of abnormal proteins in the urine of recurrent stone formers. J Urol 153:1716–1721

    Article  PubMed  CAS  Google Scholar 

  17. Hallson PC, Choong SK, Kasidas GP, Samuell CT (1997) Effects of Tamm-Horsfall protein with normal and reduced sialic acid content upon the crystallization of calcium phosphate and calcium oxalate in human urine. Br J Urol 80:533–538

    PubMed  CAS  Google Scholar 

  18. Hallson PC, Rose GA (1979) Uromucoids and urinary stone formation. Lancet 1:1000–1002

    Article  PubMed  CAS  Google Scholar 

  19. Hess B, Nakagawa Y, Coe FL (1989) Inhibition of calcium oxalate monohydrate crystal aggregation by urine proteins. Am J Physiol 257:F99–F106

    PubMed  CAS  Google Scholar 

  20. Hess B, Nakagawa Y, Parks JH, Coe FL (1991) Molecular abnormality of Tamm-Horsfall glycoprotein in calcium oxalate nephrolithiasis. Am J Physiol 260:F569–F578

    PubMed  CAS  Google Scholar 

  21. Hession C, Decker JM, Sherblom AP, Kumar S, Yue CC, Mattaliano RJ, Tizard R, Kawashima E, Schmeissner U, Heletky S (1987) Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines. Science 237:1479–1484

    Article  PubMed  CAS  Google Scholar 

  22. Hoyer JR, Seiler MW (1979) Pathophysiology of Tamm-Horsfall protein. Kidney Int 16:279–289

    Article  PubMed  CAS  Google Scholar 

  23. Huang ZQ, Sanders PW (1995) Biochemical interaction between Tamm-Horsfall glycoprotein and Ig light chains in the pathogenesis of cast nephropathy. Lab Invest 73:810–817

    PubMed  CAS  Google Scholar 

  24. Jaggi M, Nakagawa Y, Zipperle L, Hess B (2007) Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function. Urol Res 35:55–62

    Article  PubMed  CAS  Google Scholar 

  25. Jovine L, Qi H, Williams Z, Litscher E, Wassarman PM (2002) The ZP domain is a conserved module for polymerization of extracellular proteins. Nat Cell Biol 4:457–461

    Article  PubMed  CAS  Google Scholar 

  26. Knorle R, Schnierle P, Koch A, Buchholz NP, Hering F, Seiler H, Ackermann T, Rutishauser G (1994) Tamm-Horsfall glycoprotein: role in inhibition and promotion of renal calcium oxalate stone formation studied with Fourier-transform infrared spectroscopy. Clin Chem 40:1739–1743

    PubMed  CAS  Google Scholar 

  27. Kobayashi K, Fukuoka S (2001) Conditions for solubilization of Tamm-Horsfall protein/uromodulin in human urine and establishment of a sensitive and accurate enzyme-linked immunosorbent assay (ELISA) method. Arch Biochem Biophys 388:113–120

    Article  PubMed  CAS  Google Scholar 

  28. Konya E, Amasaki N, Umekawa T, Iguchi M, Kurita T (2002) Influence of urinary sialic acid on calcium oxalate crystal formation. Urol Int 68:281–285

    Article  PubMed  CAS  Google Scholar 

  29. Lieske JC, Toback FG, Deganello S (2001) Sialic acid-containing glycoproteins on renal cells determine nucleation of calcium oxalate dihydrate crystals. Kidney Int 60:1784–1791

    Article  PubMed  CAS  Google Scholar 

  30. Malek RS, Boyce WH (1973) Intranephronic calculosis: its significance and relationship to matrix in nephrolithiasis. J Urol 109:551–555

    PubMed  CAS  Google Scholar 

  31. McQueen EG (1966) Composition of urinary casts. Lancet 1:397–398

    Article  PubMed  CAS  Google Scholar 

  32. McQueen EG, Engel GB (1966) Factors determining the aggregation of urinary mucoprotein. J Clin Pathol 19:392–396

    Article  PubMed  CAS  Google Scholar 

  33. Melick RA, Quelch KJ, Rhodes M (1980) The demonstration of sialic acid in kidney stone matrix. Clin Sci (Lond) 59:401–404

    CAS  Google Scholar 

  34. Merchant ML, Cummins TD, Wilkey DW, Salyer SA, Powell DW, Klein JB, Lederer ED (2008) Proteomic analysis of renal calculi indicates an important role for inflammatory processes in calcium stone formation. Am J Physiol Renal Physiol 295:F1254–F1258

    Article  PubMed  CAS  Google Scholar 

  35. Mo L, Liaw L, Evan AP, Sommer AJ, Lieske JC, Wu XR (2007) Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both. Am J Physiol Renal Physiol 293:F1935–F1943

    Article  PubMed  CAS  Google Scholar 

  36. Nakagawa Y, Abram V, Parks JH, Lau HS, Kawooya JK, Coe FL (1985) Urine glycoprotein crystal growth inhibitors. Evidence for a molecular abnormality in calcium oxalate nephrolithiasis. J Clin Invest 76:1455–1462

    Article  PubMed  CAS  Google Scholar 

  37. Pennica D, Kohr WJ, Kuang WJ, Glaister D, Aggarwal BB, Chen EY, Goeddel DV (1987) Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein. Science 236:83–88

    Article  PubMed  CAS  Google Scholar 

  38. Porter KR, Tamm I (1955) Direct visualization of a mucoprotein component of urine. J Biol Chem 212:135–140

    PubMed  CAS  Google Scholar 

  39. Prado MJ, Nicastri AL, Costa PL, Rockman T, Tersariol IL, Nader HB, Barros RT, Prado EB (1997) The renal and hepatic distribution of Bence Jones proteins depends on glycosylation: a scintigraphic study in rats. Braz J Med Biol Res 30:865–872

    Article  PubMed  CAS  Google Scholar 

  40. Pragasam V, Kalaiselvi P, Subashini B, Sumitra K, Varalakshmi P (2005) Structural and functional modification of THP on nitration: comparison with stone formers THP. Nephron Physiol 99:28–34

    Article  Google Scholar 

  41. Qiu SR, Wierzbicki A, Orme CA, Cody AM, Hoyer JR, Nancollas GH, Zepeda S, De Yoreo JJ (2004) Molecular modulation of calcium oxalate crystallization by osteopontin and citrate. Proc Natl Acad Sci USA 101:1811–1815

    Article  PubMed  CAS  Google Scholar 

  42. Reinhart HH, Obedeanu N, Walz D, Sobel JD (1989) A new ELISA method for the rapid quantification of Tamm-Horsfall protein in urine. Am J Clin Pathol 92:199–205

    PubMed  CAS  Google Scholar 

  43. Robertson WG, Peacock M (1972) Calcium oxalate crystalluria and inhibitors of crystallization in recurrent renal stone-formers. Clin Sci 43:499–506

    PubMed  CAS  Google Scholar 

  44. Romero MC, Nocera S, Nesse AB (1997) Decreased Tamm-Horsfall protein in lithiasic patients. Clin Biochem 30:63–67

    Article  PubMed  CAS  Google Scholar 

  45. Ronco P, Brunisholz M, Geniteau-Legendre M, Chatelet F, Verroust P, Richet G (1987) Physiopathologic aspects of Tamm-Horsfall protein: a phylogenetically conserved marker of the thick ascending limb of Henle’s loop. Adv Nephrol Necker Hosp 16:231–249

    PubMed  CAS  Google Scholar 

  46. Rose GA, Sulaiman S (1982) Tamm-Horsfall mucoproteins promote calcium oxalate crystal formation in urine: quantitative studies. J Urol 127:177–179

    PubMed  CAS  Google Scholar 

  47. Rose MB (1975) Renal stone formation. The inhibitory effect of urine on calcium oxalate precipitation. Invest Urol 12:428–433

    PubMed  CAS  Google Scholar 

  48. Schnierle P (1995) A simple diagnostic method for the differentiation of Tamm-Horsfall glycoproteins from healthy probands and those from recurrent calcium oxalate renal stone formers. Experientia 51:1068–1072

    Article  PubMed  CAS  Google Scholar 

  49. Schnierle P, Hering F, Seiler H (1996) Isoelectric focusing of Tamm-Horsfall glycoproteins: a simple tool for recognizing recurrent calcium oxalate renal stone formers. Urol Res 24:79–82

    Article  PubMed  CAS  Google Scholar 

  50. Scurr DS, Robertson WG (1986) Modifiers of calcium oxalate crystallization found in urine. III. Studies on the role of Tamm-Horsfall mucoprotein and of ionic strength. J Urol 136:505–507

    PubMed  CAS  Google Scholar 

  51. Serafini-Cessi F, Bellabarba G, Malagolini N, Dall’Olio F (1989) Rapid isolation of Tamm-Horsfall glycoprotein (uromodulin) from human urine. J Immunol Methods 120:185–189

    Article  PubMed  CAS  Google Scholar 

  52. Serafini-Cessi F, Monti A, Cavallone D (2005) N-Glycans carried by Tamm-Horsfall glycoprotein have a crucial role in the defense against urinary tract diseases. Glycoconj J 22:383–394

    Article  PubMed  CAS  Google Scholar 

  53. Sheng X, Jung T, Wesson JA, Ward MD (2005) Adhesion at calcium oxalate crystal surfaces and the effect of urinary constituents. Proc Natl Acad Sci USA 102:267–272

    Article  PubMed  CAS  Google Scholar 

  54. Sheng X, Ward MD, Wesson JA (2005) Crystal surface adhesion explains the pathological activity of calcium oxalate hydrates in kidney stone formation. J Am Soc Nephrol 16:1904–1908

    Article  PubMed  CAS  Google Scholar 

  55. Stevenson FK, Cleave AJ, Kent PW (1971) The effect of ions on the viscometric and ultracentrifugal behaviour of Tamm-Horsfall glycoprotein. Biochim Biophys Acta 236:59–66

    PubMed  CAS  Google Scholar 

  56. Sumitra K, Pragasam V, Sakthivel R, Kalaiselvi P, Varalakshmi P (2005) Beneficial effect of vitamin E supplementation on the biochemical and kinetic properties of Tamm-Horsfall glycoprotein in hypertensive and hyperoxaluric patients. Nephrol Dial Transplant 20:1407–1415

    Article  PubMed  CAS  Google Scholar 

  57. Trewick AL, Rumsby G (1999) Isoelectric focusing of native urinary uromodulin (Tamm-Horsfall protein) shows no physicochemical differences between stone formers and non-stone formers. Urol Res 27:250–254

    Article  PubMed  CAS  Google Scholar 

  58. UniProt (2008) The universal protein resource (UniProt). Nucleic Acids Res 36:D190–D195

    Article  Google Scholar 

  59. van Aswegen CH, van der Merwe CA, du Plessis DJ (1990) Sialic acid concentrations in the urine of men with and without renal stones. Urol Res 18:29–33

    Article  PubMed  Google Scholar 

  60. van Rooijen JJ, Voskamp AF, Kamerling JP, Vliegenthart JF (1999) Glycosylation sites and site-specific glycosylation in human Tamm-Horsfall glycoprotein. Glycobiology 9:21–30

    Article  PubMed  Google Scholar 

  61. Verkoelen CF, Van Der Boom BG, Kok DJ, Romijn JC (2000) Sialic acid and crystal binding. Kidney Int 57:1072–1082

    Article  PubMed  CAS  Google Scholar 

  62. Webber D, Radcliffe CM, Royle L, Tobiasen G, Merry AH, Rodgers AL, Sturrock ED, Wormald MR, Harvey DJ, Dwek RA, Rudd PM (2006) Sialylation of urinary prothrombin fragment 1 is implicated as a contributory factor in the risk of calcium oxalate kidney stone formation. FEBS J 273:3024–3037

    Article  PubMed  CAS  Google Scholar 

  63. Wesson JA, Ganne V, Beshensky AM, Kleinman JG (2005) Regulation by macromolecules of calcium oxalate crystal aggregation in stone formers. Urol Res 33:206–212

    Article  PubMed  CAS  Google Scholar 

  64. Wesson JA, Ward MD (2007) Pathological Biomineralization of Kidney Stones. Elements 3:415–421

    Article  CAS  Google Scholar 

  65. Wiggins RC (1987) Uromucoid (Tamm-Horsfall glycoprotein) forms different polymeric arrangements on a filter surface under different physicochemical conditions. Clin Chim Acta 162:329–340

    Article  PubMed  CAS  Google Scholar 

  66. Williams J, Marshall RD, van HH, Vliegenthart JF (1984) Structural analysis of the carbohydrate moieties of human Tamm-Horsfall glycoprotein. Carbohydr Res 134:141–155

Download references

Acknowledgments

The authors thank Dr. Brian K. Olmsted for helpful discussions and Dr. William J. Zachowicz for performing the electrophoretic mobility (zeta potential) measurements reported in this study. This study was supported by the Veterans Affairs Merit Review Program (9305), the National Institutes of Health (NIDDK R01-DK068551), the Jacob Lemann Jr. Endowment Grant from the Medical College of Wisconsin, and the NYU Molecular Design Institute.

Author information

Author notes

  1. Pragasam Viswanathan

    Present address: Renal Research Lab, SBST, Center for Biomedical Research, VIT University, Vellore, 632 014, Tamilnadu, India

  2. Jeffrey D. Rimer

    Present address: Department of Chemical and Biomolecular Engineering, University of Houston, 4800 Calhoun Ave., S222 Engineering Bldg. 1, Houston, TX, 77204, USA

Authors and Affiliations

  1. The Nephrology Division of the Medical College of Wisconsin, Department of Veterans Affairs Medical Center, 111K, 5000 West National Ave, Milwaukee, 53295, WI, USA

    Pragasam Viswanathan, Ann M. Kolbach, Jack G. Kleinman & Jeffrey A. Wesson

  2. Department of Chemistry, Molecular Design Institute, New York University, 100 Washington Ave, SE, New York, NY, USA

    Jeffrey D. Rimer & Michael D. Ward

Authors
  1. Pragasam Viswanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey D. Rimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ann M. Kolbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael D. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jack G. Kleinman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeffrey A. Wesson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michael D. Ward or Jeffrey A. Wesson.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material (DOC 674 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Viswanathan, P., Rimer, J.D., Kolbach, A.M. et al. Calcium oxalate monohydrate aggregation induced by aggregation of desialylated Tamm-Horsfall protein. Urol Res 39, 269–282 (2011). https://doi.org/10.1007/s00240-010-0353-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00240-010-0353-7

Keywords

Search

Navigation