Skip to main content

Advertisement

Log in

Urinary levels of matrix metalloproteinases and their tissue inhibitors in nephrotic children

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The aim of this study was to determine the effects of cyclosporine A (CyA) on urinary levels of matrix metalloproteinase 2 and 9 (MMP2, MMP9) and their tissue inhibitors 1 and 2 (TIMP1, TIMP2) in steroid-dependent nephrotic syndrome (SDNS). The study group (1) consisted of 18 children SDNS aged 3.5–17.0 years treated with CyA. All NS children were examined three times: (A) at proteinuria relapse, before CyA treatment, (B) after 6 months, and (C) after 12 months of CyA administration. The control group (2) consisted of 18 healthy children. Serum CyA level was assessed by immunofluorescence. Enzyme-linked immunosorbent assay kits for total human MMP2 and 9 and TIMP1 and 2 were obtained from R&D Systems. Compared with healthy controls, urinary MMP9/Cr in NS children before CyA was on the same level and increased during CyA treatment, and urinary TIMP1/Cr was twice as high and increased significantly during CyA treatment. MMP9/TIMP1 in NS children treated with CyA increased, but the difference was not statistically significant. Urinary MMP2/Cr was similar, and urinary TIMP2/Cr was significantly higher in children treated with CyA (p < 0.01). The MMP2/TIMP2 ratio in NS children treated with CyA was significantly lower in comparison with healthy controls (p < 0.01). A negative correlation was noted between urinary MMP2/TIMP2 ratio and serum CyA in NS children (r = −0.541, p < 0.01). An imbalance within the MMP2 and TIMP2 and MMP9 and TIMP1 system may play a role in the pathogenesis CyA nephropathy.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ehrich JH, Brodehl J (1993) Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Pädiatrische Nephrologie. Eur J Pediatr 152:357–361

    Article  CAS  Google Scholar 

  2. Andoh TF, Bennett WM (1998) Chronic cyclosporine nephrotoxicity. Curr Opin Nephrol Hypertens 7:265–270

    Article  CAS  Google Scholar 

  3. Taler SJ, Textor SC, Canzanello VJ, Schwartz L (1999) Cyclosporin-induced hypertension: incidence, pathogenesis and management. Drug Saf 20:437–449

    Article  CAS  Google Scholar 

  4. Antonovych TT, Sabnis SG, Austin HA, Palestine AG, Balow JE, Nussenblatt RB, Helfrich GB, Foegh ML, Alijani MR (1998) Cyclosporine A-induced arteriolopathy. Transplant Proc 20:951–958

    Google Scholar 

  5. Ruiz-Ortega M, Egido J (1997) Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblast. Kidney Int 52:1497–1499

    Article  CAS  Google Scholar 

  6. Schiffer M, Von Gersdorff G, Bitzer M, Susztak K, Bottinger EP (2000) S-mad proteins and transforming growth factor-beta signaling. Kidney Int 58:45–52

    Article  Google Scholar 

  7. Han SY, Jee YH, Han KH, Kang YS, Kim HK, Han JY, Kim YS, Cha DR (2006) An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy. Nephrol Dial Transplant 21:2406–2416

    Article  CAS  Google Scholar 

  8. Iurlaro M, Vacca A, Minischetti M, Ribatti D, Pellegrino A, Sardanelli A, Giacchetta F, Dammacco F (1998) Antiangiogenesis by cyclosporine. Exp Hematol 26:1215–1222

    CAS  PubMed  Google Scholar 

  9. Furness PN (1996) Extracellular matrix and the kidney. J Clin Pathol 49:355–359

    Article  CAS  Google Scholar 

  10. Dollery CM, McEwan JR, Henney AM (1995) Matrix metalloproteinases and cardiovascular disease. Circ Res 77:863–868

    Article  CAS  Google Scholar 

  11. Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–494

    Article  CAS  Google Scholar 

  12. Tryggvason K, Huhtala P, Hoyhtya M, Hujanen E, Hurskainen T (1992) 70 K type IV collagenase (gelatinase). Matrix (Suppl 1):45–50

  13. Lenz O, Elliot SJ, Stetler-Stevenson WG (2000) Matrix metalloproteinases in renal development and disease. J Am Soc Nephrol 11:574–581

    CAS  PubMed  Google Scholar 

  14. Woessner JF Jr (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145–2154

    Article  CAS  Google Scholar 

  15. Striker GE, He CJ, Liu ZH, Yang CC, Zalups R, Esposito C, Striker LJ (1995) Pathogenesis of non-immune glomerulosclerosis: Studies in animal and potential application to man. Lab Invest 73:1–10

    Google Scholar 

  16. Ross R (1999) Atherosclerosis: An inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  Google Scholar 

  17. Powell WC, Matrisian LM (1996) Complex roles of matrix metalloproteinases in tumor progression. Curr Top Microbiol Immunol 213:1–21

    CAS  PubMed  Google Scholar 

  18. Funck RC, Wilke A, Rupp H, Brilla CG (1997) Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease. Adv Exp Med Biol 432:35–44

    Article  CAS  Google Scholar 

  19. Laviades C, Varo N, Fernandez J, Mayor G, Gil MJ, Monreal I, Diez J (1998) Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 98:535–540

    Article  CAS  Google Scholar 

  20. Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F, Ueno T, Sugi K, Imaizumi T (1998) Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 32:368–372

    Article  CAS  Google Scholar 

  21. Singhal PC, Sagar S, Garg P (1996) Simulated glomerular pressure modulates mesangial cell 72 kDa metalloproteinase activity. Connect Tissue Res 33:257–263

    Article  CAS  Google Scholar 

  22. Duymelinck C, Deng JT, Dauwe SE, De Broe ME, Verpooten GA (1998) Inhibition of the matrix metalloproteinase system in a rat model of chronic cyclosporine nephropathy. Kidney Int 54:804–818

    Article  CAS  Google Scholar 

  23. Abrass CK (1995) Diabetic nephropathy. Mechanisms of mesangial matrix expansion. West J Med 162:318–321

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Steinmann-Niggli K, Ziswiler R, Kung M, Marti HP (1998) Inhibition of matrix metalloproteinases attenuates anti-Thy1.1 nephritis. J Am Soc Nephrol 9:397–407

    CAS  PubMed  Google Scholar 

  25. Akiyama K, Shikata K, Sugimoto H, Matsuda M, Shikata Y, Fujimoto N, Obata K, Matsui H, Makino H (1997) Changes in serum concentrations of matrix metalloproteinases, tissue inhibitors of metalloproteinases and type IV collagen in patients with various types of glomerulonephritis. Res Commun Mol Pathol Pharmacol 95:115–128

    CAS  PubMed  Google Scholar 

  26. Koide H, Nakamura T, Ebihara I, Tomino Y (1996) Increased mRNA expression of metalloproteinase-9 in peripheral blood monocytes from patients with immunoglobulin A nephropathy. Am J Kidney Dis 28:32–39

    Article  CAS  Google Scholar 

  27. Esposito C, Foschi A, Parrilla B, Cornacchia F, Fasoli G, Plati AR, De Mauri A, Mazzullo T, Scudellaro R, Dal Canton A (2004) Effect of calcineurin inhibitors on extracellular matrix turnover in isolated human glomeruli. Transplant Proc 36:695–697

    Article  CAS  Google Scholar 

  28. Bianchi R, Rodella L, Rezzani R (2003) Cyclosporine A up-regulates expression of matrix metalloproteinase 2 and vascular endothelial growth factor in rat heart. Int Immunopharmacol 3:427–433

    Article  CAS  Google Scholar 

  29. Robert V, Besse S, Sabri A, Silvestre JS, Assayag P, Nguyen VT, Swynghedauw B, Delcayre C (1997) Differential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart. Lab Invest 76:729–738

    CAS  PubMed  Google Scholar 

  30. Rezzani R, Angoscini P, Rodella L, Bianchi R (2002) Alterations induced by cyclosporine A in myocardial fibers and extracellular matrix in rat. Histol Histopathol 17:761–766

    CAS  PubMed  Google Scholar 

  31. Murphy G, Stanton H, Cowell S, Butler G, Knauper V, Atkinson S, Gavrilovic J (1999) Mechanisms for pro matrix metalloproteinase activation. APMIS 107:38–44

    Article  CAS  Google Scholar 

  32. Nguyen M, Arkell J, Jackson CJ (2001) Human endothelial gelatinases and angiogenesis. Int J Biochem Cell Biol 33:960–970

    Article  CAS  Google Scholar 

  33. McMorrow T, Gaffney MM, Slattery C, Campbell E, Ryan MP (2005) Cyclosporine A induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells. Nephrol Dial Transplant 20:2215–2225

    Article  CAS  Google Scholar 

  34. Horstrup JH, Gehrmann M, Schneider B, Ploger A, Froese P, Schirop T, Kampf D, Frei U, Neumann R, Eckardt KU (2002) Elevation of serum and urine levels of TIMP1 and tenascin in patients with renal disease. Nephrol Dial Transplant 17:1005–1013

    Article  Google Scholar 

  35. Eddy AA, Giachelli CM (1995) Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. Kidney Int 47:1546–1557

    Article  CAS  Google Scholar 

  36. Jones CL, Buch S, Post M, McCulloch L, Liu E, Eddy AA (1992) Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats. Am J Pathol 141:1381–1396

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Carome MA, Striker LJ, Peten EP, Moore J, Yang CW, Stetler-Stevenson WG, Striker GE (1993) Human glomeruli express TIMP1 mRNA and TIMP2 protein and mRNA. Am J Physiol 264:F923–F929

    CAS  PubMed  Google Scholar 

  38. Engelmyer E, van Goor H, Edwards DR, Diamond JR (1995) Differential mRNA expression of renal cortical tissue inhibitor of metalloproteinase-1, -2, and -3 in experimental hydronephrosis. J Am Soc Nephrol 5:1675–1683

    CAS  PubMed  Google Scholar 

  39. Klotz S, Danser AH, Foronjy RF, Oz MC, Wang J, Mancini D, D'Armiento J, Burkhoff D (2007) The impact of angiotensin-converting enzyme inhibitor therapy on the extracellular collagen matrix during left ventricular assist device support in patients with end-stage heart failure. J Am Coll Cardiol 49:1166–1174

    Article  CAS  Google Scholar 

  40. Li H, Simon H, Bocan TM, Peterson JT (2000) MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition. Cardiovasc Res 46:298–306

    Article  CAS  Google Scholar 

  41. Guo XG, Uzui H, Mizuguchi T, Ueda T, Chen JZ, Lee JD (2008) Imidaprilat inhibits matrix metalloproteinase-2 activity in human cardiac fibroblasts induced by interleukin-1beta via NO-dependent pathway. Int J Cardiol 126:414–420

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anna M. Wasilewska.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wasilewska, A.M., Zoch-Zwierz, W.M. Urinary levels of matrix metalloproteinases and their tissue inhibitors in nephrotic children. Pediatr Nephrol 23, 1795–1802 (2008). https://doi.org/10.1007/s00467-008-0881-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-008-0881-3

Keywords

Navigation